Substituted amine derivatives having antihyperlipemia activity

ABSTRACT

Substituted amine derivatives represented by the general formula ##STR1## wherein Q is -C-D-E- F-G-M- or -N-H-I-J-K-L- [C, D, E, F, G, H, I, J, K and L are each O, S, a carbonyl group, -CHR 2  -, -R b  = or -NR c  - (R a , R b  and R c  are each H or a lower alkyl group), M and N are each an aromatic ring of 5-6 members optionally having a halogen, OH, LN, a lower alkyl group or a lower alkoxy group, provided that L is not O, S, or -NR c  -]; R is a heterocyclic ring of 5-6 members; R 1  is H, a lower alkyl group, a lower haloalkyl group, a lower alkenyl group, a lower alkynyl group or a cycloalkyl group; R 2 , R 3 , R 4 , R 5  R 6  and R 7  are each H, a halogen or a lower alkyl group or two of them denote a single bond; R 8  and R 9  are each F, CF 3  or a lower alkyl group or are a cycloalkane in combination thereof; and R 10  is H, F, CF.sub. 3 an acetoxy group, a lower alkyl group or a lower alkoxy group. These compounds inhibit biosynthesis of cholesterol in mammals by inhibiting their squalene epoxidase, and thereby lower their blood cholesterol values. Therefore, these compounds are expected to be effective as an agent for treatment and prophylaxis of diseases caused by excess of cholesterol, for example, obesity, hyperlipemia and arteriosclerosis and heart and encephalic diseases accompanying them.

This application is a continuation of application Ser. No. 07/672,430,filed Mar. 20, 1991, now abandoned.

DETAILED DESCRIPTION OF THE INVENTION

This invention relates to novel substituted amine derivatives, and moredetailedly relates to substituted amine derivatives and their contoxicsalts useful in the medicinal field, particularly in the field oftreatment and prophylaxis of hypercholesterolemia, hyperlipemia andarteriosclerosis, and their preparation method and their use.

Recently, increase of occurrence frequency of arteriosclerosis andvarious coronary and encephalic artery system diseases following it, dueto aging of the population and change of food, life, etc., have beenpointed out. Various factors were considered as stimulants ofarteriosclerosis, and particularly, increase of blood cholesterol is oneof the most dangerous factors. Thus, blood cholesterol-lowering agentsare effective for prophylaxis and treatment of arteriosclerosis (AgentsUsed to Treat Hyperlipidemia, Drug Evaluations 6th. edition 903-926(1986)). Further, among these blood cholesterol-lowering agents, agentswhich inhibit biosynthesis of cholesterol in the living body are highlyrated due to their clear action mechanism and strong drug action (Proc.Natl. Acad. Sci., 77, 3957 (1980)). However, since many of the so farknown cholesterol biosynthesis-inhibiting agents are inhibitors in theearly stage or later stage of the cholesterol biosynthesis steps, thereare problems, for example, that, when they inhibit biosynthesis ofcholesterol, they simultaneously inhibit formation of various otherphysiologically important biological products, and further accumulationof precursors formed by the inhibition becomes a cause of otherdiseases.

Previously, the present inventors reported that a series of substitutedallylamine derivatives selectively inhibit squalene epoxidase positionedat the middle stage of the cholesterol biosynthesis system of mammals,and therefore are useful as a blood cholesterol-lowering agent having adifferent action mechanism from the known cholesterolbiosynthesis-inhibiting agents (See =Japanese Patent Application No.296840/1988, EP-A-318860, WO 90/5132 (PCT/JP89/00522)). As forinhibitors of mammal squalene epoxidase, several reports were madelately besides those by the present inventors, but any of the compoundsdescribed therein only has a very low activity (J. Chem. Research(s)18-19 (1988); J. Am. Chem. Soc., 111, 1508-1510 (1989); J. Med. Chem.,32, 2152-2158 (1989); Japanese Laid-Open Patent Publication No.3144/1989).

The major object of the invention is to provide anantihypercholesterolemia agent, an antihyperlipemia agent and an agentfor the treatment and prophylaxis of arteriosclerosis each having highersafety and excellent anticholesterol action, compared to the knowndrugs.

As described above, the present inventors previously reported that aseries of substituted allylamine derivatives selectively inhibit mammalsqualene epoxidase and have a strong anticholesterol action (JapanesePatent Application No. 296840/1988, EP-A-318860 and WO 90/5132 (PCT/JP89/0052)).

This time, as a result of vigorous study, it was found that thesubstituted amine derivatives represented by the following generalformula [I] have further excellent characteristics compared to the groupof the previously reported compounds, and the present invention wascompleted.

Thus, according to the invention, substituted amine derivativesrepresented by the following general formula and their nontoxic saltsare provided: ##STR2## wherein,

R denotes a 5- or 6-membered heterocyclic group containing 1 to 4 heteroatoms selected from the group consisting of nitrogen atom(s), oxygenatom(s) and sulfur atom(s);

Q denotes (a) a group represented by the formula: ##STR3## wherein C, D,E, F and G are the same or different and each denotes an oxygen atom,sulfur atom, carbonyl group, group represented by the formula --CHR^(b)--, group represented by the formula --CR^(c) =or group represented bythe formula --NR^(d) --, wherein R^(b), R^(c) and R^(d) are the same ordifferent and each denotes a hydrogen atom or lower alkyl group; A¹denotes a methine group, nitrogen atom, oxygen atom or sulfur atom; B¹denotes a group which may contain one or two hetero atoms selected fromthe group consisting of nitrogen atom(s), oxygen atom(s) and sulfuratom(s) and forms a 5- or 6- membered aromatic ring together with theadjacent carbon atoms and A¹ ; and 12¹ denotes a hydrogen atom, halogenatom, hydroxyl group, cyano group, lower alkyl group or lower alkoxygroup, provided that except that each pair of C and F, C and G, or D andG are the same or different and can denote oxygen atom(s), sulfuratom(s) or group(s) represented by the formula --NR^(d) --, it isimpossible that at least two of C, D, E, F and G simultaneously denoteoxygen atom(s), sulfur atom(s) or group(s) represented by the formula--NR^(d), and it is impossible that at least two of C, D, E, F and Gsimultaneously denote carbonyl groups, and further when double bond(s)and oxygen atom(s), sulfur atom(s) or group(s) represented by theformula --NR^(d) --coexist in the chain formed by C, D, E, F and G, theydo not adjoin one another, or (b) a group represented by the formula:##STR4## wherein A² denotes a methine group, nitrogen atom, oxygen atomor sulfur atom; B² denotes a group which may contain one or two heteroatoms selected from the group consisting of nitrogen atom(s), oxygenatom(s) and sulfur atom(s) and forms a 5- or 6-membered aromatic ringtogether with the adjacent carbon atoms and A² ; H, I, J and K are thesame or different and each denotes an oxygen atom, sulfur atom, carbonylgroup, group represented by the formula --CHR^(f) --, group representedby the formula --CR^(g) =or group represented by the formula --NR^(h)--, wherein R^(f), R^(g) and R^(h) are the same or different and eachdenotes a hydrogen atom or lower alkyl group; L denotes a carbonylgroup, group represented by the formula --CHR^(i) --or group representedby the formula --CR^(j) =, wherein R^(i) and R^(j) are the same ordifferent and each denotes a hydrogen atom or lower alkyl group; andR^(e) denotes a hydrogen atom, halogen atom, hydroxyl group, cyanogroup, lower alkyl group or lower alkoxy group, provided that exceptthat H and K are the same or different and each can denote an oxygenatom, sulfur atom or group represented by the formula --NR^(h) --, it isimpossible that at least two of H, I, J and K simultaneously denoteoxygen atom(s), sulfur atom(s) or group(s) represented by the formula--NR^(h) --, and it is impossible that at least two of H, I, J and Ksimultaneously denote carbonyl groups, and further when double bond(s)and oxygen atom(s), sulfur atom(s) or group(s) represented by theformula --NR^(h) --coexist in the chain formed by H, I, J, K and L, theydo not adjoin one another;

R¹ denotes a hydrogen atom, lower alkyl group, lower haloalkyl group,lower alkenyl group, lower alkynyl group or cycloalkyl group;

R², R³, R⁴ and R⁵ are the same or different and each denotes a hydrogenatom, halogen atom or lower alkyl group, or R² and R⁴ and/or R³ and R⁵combine to denote a single bond;

R⁶ and R⁷ are the same or different and each denotes a hydrogen atom,halogen atom or lower alkyl group, or R⁶ and R⁷ combine to denote asingle bond;

R⁸ and R⁹ are the same or different and each denotes a fluorine atom,trifluoromethyl group or lower alkyl group, or R⁸ and R⁹ combine todenote a group to form cycloalkane together with the adjacent carbonatom;

R¹⁰ denotes a hydrogen atom, fluorine atom, trifluoromethyl group,acetoxy group, lower alkyl group or lower alkoxy group.

Compounds of the above formula [I] in the invention inhibit mammalsqualene epoxidase extremely selectively and strongly and are useful asa drug for prophylaxis or treatment of hypercholesterolemia,hyperlipemia, arteriosclerosis, etc.

Described below are definitions of various terms referred to in thedescription of this specification and their specific examples.

The term "lower" is used to mean that the carbon number of the group orcompound to which this term is attached is 6 or less, preferably 5 orless.

Thus, a lower alkyl group includes a straight-chain or branched alkylgroup having 1 to 6, preferably 1 to 3 carbon atoms such as a methyl,ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl,pentyl, isopentyl, neopentyl or hexyl group; a lower haloalkyl groupincludes a haloalkyl group having 1 to 3 halogen atoms and 1 to 4 carbonatoms such as a trifluoromethyl, 2-fluoroethyl, 2-chloroethyl,2,2,2-trifluoroethyl, 3-fluoropropyl or 2-fluoro-2-methylpropyl,4-fluorobutyl group; a lower alkenyl group includes a straight-chain orbranched alkenyl group having 3 to 5 carbon atoms such as an allyl,2-methyl-2-propenyl, 2-butenyl, 3-butenyl or 2-pentenyl group; a loweralkynyl group includes a straight-chain or branched alkynyl group having3 to 5 carbon atoms such as a propargyl, 2-butynyl, 3-butynyl,1-methyl-2-butynyl or 2-pentynyl group; and a lower alkoxy groupincludes straight-chain or branched alkoxy group having 1 to 5 carbonatoms such as a methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy,sec-butoxy, tert-butoxy or pentoxy group.

A cycloalkyl group and a cycloalkane include a cycloalkyl group and acycloalkane each having 3 to 6 carbon atoms, respectively, andspecifically, examples of the cycloalkyl group are cyclopropyl,cyclobutyl, cyclopentyl and cyclohexyl groups and examples of thecycloalkane are cyclopropane, cyclobutane, cyclopentane and cyclohexane.

Halogen atoms include fluorine, chlorine, bromine and iodine atoms.

In order to further specifically disclose compounds of the inventionrepresented by the above general formula [I], the various symbols usedin the formula [I]are further detailedly described mentioning theirpreferred specific examples

Examples of the 5- or 6- membered hetero cyclic group, symbolized by R,containing 1 to 4 hetero atoms selected from the group consisting ofnitrogen atom(s), oxygen atom(s) and sulfur atom(s) include pyrrolyl,furyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl,imidazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl,furazanyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl and triazinylgroups and other aromatic heterocyclic groups; and dihydrothienyl,tetrahydrothienyl, pyrrolinyl, pyrrolidinyl, oxazolinyl, oxazolidinyl,isoxazolinyl, isoxazolidinyl, thiazolinyl, thiazolidinyl,isothiazolinyl, isothiazolidinyl, 1, 2-dithiolanyl, 1, 3-dithiolanyl, 1,2-dithiolyl, 1, 3-dithiolyl, dihydrothiopyranyl, tetrahydrothiopyranyl,1, 4-dithianyl, 1, 4-dithiinyl, 1, 4-oxathiinyl and thiomorpholinylgroups and other nonaromatic heterocyclic groups. Among them, preferredare thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl,imidazolyl, pyridyl and dihydrothienyl groups, etc., and particularlypreferred are 3-thienyl, 1-pyrrolyl, 5-oxazolyl, 4-isoxazolyl,5-isoxazolyl, 4-thiazolyl, 5-thiazolyl, 3-isothiazolyl, 4-isothiazolyl,5-isothiazolyl, 3-pyridyl, 2, 3-dihydro-4-thienyl and 2,5-dihydro-3-thienyl groups, etc.

In the group symboled by R and represented by (a) the formula: ##STR5##or (b) the formula: ##STR6## , the aromatic ring represented by theformula; ##STR7## or the formula: ##STR8## is an aromatic ringoptionally containing 1 to 3 hetero atoms selected from the groupconsisting of nitrogen atom(s), oxygen atom(s) and sulfur atom(s), suchas a benzene, pyrrole, furan, thiophene, oxazole, isoxazole, thiazole,isothiazole, imidazole, 1,3,4-oxadiazole, 1,3,4-thiaziazole, pyridine,pyridazine, pyrimidine, pyrazine or triazine ring. Further, in theformula of the above (a), specific examples of the chained group formedby C, D, E, F and G include those represented by the following formulae:--(CHR^(b))₅ --, --CR^(c) ═CR^(c) (CHR^(b))₃ --, --CHR^(b) CR^(c)═CR^(c) (CHR^(b))₂ --, --(CHR^(b))₂ CR^(c) ═CR^(c) CHR^(b) --,--CHR^(b))₃ CR^(c) ═CR^(c) --, --(CR^(c) ═CR^(c))₂ CHR⁶ --, --CHR^(b)(CR^(c) ═CR^(c))₂ --, --CR^(c) ═CR^(c) CHR^(b) CR^(c) ═CR^(c) --,--O(CHR^(b))₄ --, --S(CHR^(b))₄ --, --NR^(d) (CHR.sup. b)₄ --, --CHR^(b)O(CHR^(b))₃ --, --CHR^(b) S(CHR^(b))₃ --, --CHR^(b) NR^(d) (CHR^(b))₃--, --(CHR^(b))₂ O(CHR^(b))₂ --, --(CHR^(b))₂ S(CHR^(b) )₂ --,--(CHR^(b))₂ NR^(d) (CHR^(b))₂ --, --(CHR^(b))₃ OCHR^(b) --,--(CHR^(b))₃ SCHR^(b) --, --(CHR^(b))₃ NR^(d) CHR^(b) --, --(CHR^(b))₄O--, --(CHR^(b))₄ S--, --(CHR^(b)) ₄ NR^(d) --, --O(CHR^(b))₂ OCHR^(b)--, --O(CHR^(b))₂ SCHR^(b) --, --O(CHR^(b))₂ NR^(d) CHR^(b) --,--S(CHR^(b))₂ OCHR^(b) --, --S(CHR^(b))₂ SCHR^(b) --, --S(CHR^(b))₂NR^(d) CHR^(b) --, --NR^(d) (CHR^(b))₃ O--, --NR^(d) (CHR^(b))₂SCHR.sup. b --, --NR^(d) (CHR^(b))₂ NR^(d) CHR ^(b) --, --CHR^(b)O(CHR^(b))₂ O--, --CHR^(b) O(CHR^(b))₂ S--, --CHR^(b) O(CHR^(b))₂ NR^(d)--, --CHR^(b) S(CHR^(b))₂ O--, --CHR^(b) S(CHR^(b))₂ S--, --CHR^(b)S(CHR^(b))₂ NR^(d) --, --CHR^(b) NR^(d) (CHR^(b))₂ O--, --CHR^(b) NR^(d)(CHR^(b))₂ S--, --CHR^(b) NR^(d) (CHR^(b))₂ NR^(d) --, --O(CHR^(b))₃O--, --O(CHR^(b))₃ S--, --O(CHR^(b))₃ NR^(d) --, --S(CHR^(b))₃ O--,--S(CHR^(b))₃ S--, --S(CHR^(b))₃ NR^(d) --, --NR^(d) (CHR^(b))₃ O--,--NR^(d) (CHR^(b))₃ S--, --NR^(d) (CHR^(b))₃ NR^(d) --, --CO(CHR^(b))₄--,--CHR^(b) CO(CHR^(b))₃ --, --(CHR^(b))₂ CO(CHR^(b))₂ --, --(CHR^(b))₃COCHR^(b) --, --(CHR^(b))₄ CO--, --COCR^(c) ═CR^(c) (CHR^(b))₂ --,--CO(CHR^(b))₂ CR^(c) ═CR^(c) --, --CO(CR^(c) ═CR^(c))₂ --, --CHR^(b)COCR^(c) ═CR^(c) CHR^(b) --, --CR^(c) ═CR^(c) CO(CHR^(b))₂ --,--(CHR^(b))₂ COCR^(c) ═CR^(c) --, --CR^(c) ═CR^(c) COCR^(c) ═CR^(c) --,--CHR^(b) CR^(c) ═CR^(c) COCHR^(b) --, --(CHR^(b))₂ CR^(c) ═CR^(c) CO--,--CR^(c) ═CR^(c) (CHR^(b))₂ CO--, --(CR^(c) ═CR^(c))₂ CO--.--OCO(CHR^(b))₃ --, --SCO(CHR^(b))₃ --, --NR^(d) CO(CHR^(b))₃ --,--OCHR^(b) CO(CHR^(b) )₂ --, --SCHR^(b) CO(CHR^(b))₂ --, --NR^(d)CHR^(b) CO(CHR^(b))₂ --, --O(CHR^(b))COCHR^(b) --, --S(CHR^(b))₂COCHR^(b) --, --NR^(d) (CHR^(b))₂ COCHR^(b) --, --O(CHR^(b))₃ CO--,--S(CHR^(b))₃ CO--, --NR^(d) (CHR^(b))₃ CO--, --OCHR^(b) CR^(c) ═CR^(c)CHR^(b) --, --SCHR^(b) CR^(c) ═CR^(c) CHR^(b) --, --NR^(d) CHR^(b)CR^(c) ═CR^(c) CHR^(b) --, --OCOCR^(c) ═CR^(c) CHR^(b) --, --SCOCR^(c)═CR^(c) CHR^(b) --, --NR^(d) COCR^(c) ═CR^(c) CHR^(b) --, --OCHR^(b)CR^(c) ═CR^(c) CO--, --SCHR^(b) CR^(c) ═CR^(c) CO--, --NR^(d) CHR^(b)CR^(c) ═CR^(c) CO--, --O(CHR^(b))₂ CR^(c) ═CR^(c) --, --S(CHR^(b))₂CR^(c) ═CR^(c) -- , --NR^(d) (CHR^(b))₂ CR^(c) ═CR^(c) --, --OCHR^(b)COCR^(c) ═CR^(c) --, --SCHR^(b) COCR^(c) ═CR^(c) --, --NR^(d) CHR^(b)COCR^(c) ═CR^(c) --, --COO(CHR^(b))₃ --, --COS(CHR^(b))₃ --, --CONR^(d)(CHR^(b))₃ --, --CHR^(b) OCO(CHR^(b))₂ --, --CHR^(b) SCO(CHR )₂ --,--CHR^(b) NR^(d) CO (CHR^(b))₂ --, --CHR^(b) OCHR^(b) COCHR^(b) --,--CHR^(b) SCHR^(b) COCHR^(b) --, --CHR^(b) NR^(d) CHR^(b) COCHR^(b) --,--CHR^(b) O(CHR^(b))₂ CO --, --CHR^(b) S(CHR^(b))₂ CO--, --CHR^(b)NR^(d) (CHR^(b))₂ CO--, --CHR^(b) OCHR^(b) CR^(c) ═CR ^(c) --, --CHR^(b)SCHR^(b) CR^(c) ═CR^(c) --, --CHR^(b) NR^(d) CHR^(b) CR^(c) ═CR^(c) --,--COOCHR^(b) CR^(c) ═CR^(c) --, --COSCHR^(b) CR^(c) ═CR^(c) --,--CONR^(d) CHR^(b) CR^(c) ═CR ^(c) --, --CHR^(b) OCOCR^(c) ═CR^(c) --,--CHR^(b) SCOCR^(c) ═CR^(c) --, --CHR^(b) NR^(d) COCR^(c) ═CR ^(c) --,--COCHR^(b) O(CHR^(b))₂ --, --COCHR^(b) S(CHR^(b))₂ --, --COCHR^(b)NR^(d) (CHR^(b))₂ --, --CHR^(b) COO(CHR^(b))₂ --, --CHR^(b)COS(CHR^(b))₂ --, --CHR^(b) CONR^(d) (CHR^(b))₂ --, --(CHR^(b))₂OCOCHR^(b) --, --(CHR^(b))₂ SCOCHR^(b) --, --(CHR^(b))₂ NR^(d) COCHR^(b)--, --(CHR^(b))₂ OCHR^(b) CO--, --(CHR^(b))₂ SCHR^(b) CO--, --(CHR^(b))₂NR^(d) CHR^(b) CO--, --CO(CHR^(b))₂ OCHR^(b) --, --CO(CHR^(b))₂ SCHR^(b)--, --CO(CHR^(b) )₂ NR^(d) CHR^(b) --, --CHR^(b) COCHR^(b) OCHR^(b) --,--CHR^(b) COCHR^(b) SCHR^(b) --, --CHR^(b) COCHR^(b) NR^(d) CHR^(b) --,(CHR^(b))₂ COOCHR^(b) --, --(CHR^(b))₂ COSCHR^(b) --, --(CHR^(b))₂CONR^(d) CHR^(b) --, --(CHR^(b))₃ OCO--, --(CHR^(b))₃ SCO--,--(CHR^(b))₃ NR^(d) CO--, --CR^(c) ═CR^(c) CHR^(b) OCHR^(b) --, --CR^(c)═CR^(c) CHR^(b) SCHR ^(b) --, --CR^(c) ═CR^(c) CHR^(b) NR^(d) CHR^(b)--, --CR^(c) ═CR^(c) COOCHR^(b) --, --CR^(c) ═CR^(c) ═COSCHR^(b) --,--CR^(c) ═CR^(c) CONR^(d) CHR^(b) --, --CR^(c) ═CR^(c) CHR^(b) OCO--,--CR^(c) ═CR^(c) CHR^(b) SCO--, --CR^(c) ═CR^(c) CHR^(b) NR^(d) CO--,--CO(CHR^(b))₃ O--, --CO(CHR^(b))₃ S--, --CO(CHR^(b))₃ NR^(d) --,--CHR^(b) CO(CHR^(b))₂ O--, --CHR^(b) CO(CHR^(b))₂ S--, --(CHR^(b))₂NR^(d) --, --(CHR^(b))₂ COCHR^(b) O--, --(CHR^(b))₂ COCHR^(b) S--,--(CHR^(b))₂ COCHR^(b) NR^(d) --, --(CHR^(b))₃ COO--, --(CHR^(b))₃COS--, --(CHR^(b))₃ CONR^(d) --, --CR^(c) ═CR^(c) (CHR^(b))₂ O--,--CR^(c) ═CR^(c) (CHR^(b)) ₂ S--, --CR^(c) ═CR^(c) (CHR^(b))₂ NR^(d) --,--CR^(c) ═CR^(c) COCHR^(b) O--, --CR^(c) ═CR^(c) COCHR^(b) S--, --CR^(c)═CR^(c) COCHR^(b) NR^(d) --, --CHR^(b) CR^(c) ═CR^(c) CHR^(b) O--,--CHR^(b) CR^(c) ═CR^(c) CHR^(b) S--, --CHR^(b) CR^(c) ═CR^(c) CHR^(b)NR^(d) --, --COCR^(c) ═CR^(c) CHR^(b) O--, --COCR^(c) ═CR^(c) CHR^(b)S--, --COCR^(c) ═CR^(c) CHR^(b) NR^(d) --, --CHR^(b) CR^(c) ═CR COO--,--CHR^(b) CR ═CR^(c) COS--, --CHR^(b) CR^(c) ═CR^(c) CONR^(d) --,--OCOCHR^(b) OCHR^(b) --, --OCOCHR^(b) SCHR^(b) --, --OCOCHR^(b) NR^(d)CHR^(b) --, --SCOCHR^(b) OCHR^(b) --, --SCOCHR^(b) SCHR^(b) --,--SCOCHR^(b) NR^(d) CHR^(b) --, --NR^(d) COCHR^(b) OCHR^(b) --, --NR^(d)COCHR^(b) SCHR^(b) --, --NR^(d) COCHR^(b) NR^(d) CHR^(b) --, --OCHR^(b)COOCHR^(b) -- , --OCHR^(b) COSCHR^(b) --, --OCHR^(b) CONR^(d) CHR^(b)--, --SCHR^(b) COOCHR^(b) --, --SCHR^(b) COSCHR^(b) --, --SCHR^(b)CONR^(d) CHR^(b) --, --NR^(d) CHR^(b) COOCHR^(b) --, --NR^(d) CHR^(b)COSCHR^(b) --, --NR^(d) CHR^(b) CONR^(d) CHR^(b) --, --O(CHR^(b))₂OCO--, --O(CHR^(b))₂ SCO--, --O(CHR^(b))₂ NR^(d) CO--, --S(CHR^(b))₂OCO--, --S(CHR^(b))₂ SCO--, --S(CHR^(b))₂ NR^(d) CO--, --NR^(d)(CHR^(b))₂ OCO--, --NR^(d) (CHR^(b))₂ SCO--, --NR^(d) (CHR^(b))₂ NR^(d)CO--, --COO(CHR^(b))₂ O--, --COO(CHR^(b))₂ S--, --COO(CHR^(b))₂ NR^(d)--, --COS(CHR^(b))₂ O--, --COS(CHR^(b))₂ S--, --COS(CHR^(b))₂ NR^(d) --,--CONR^(d) (CHR^(b))₂ O--, -- CONR^(d) (CHR^(b))₂ S--, --CONR^(d)(CHR^(b))₂ NR^(d) --, --CHR^(b) OCOCHR^(b) O--, --CHR^(b) OCOCHR^(b)S--, --CHR^(b) OCOCHR^(b) NR^(d) --, --CHR^(b) SCOCHR^(b) O--, --CHR^(b)SCOCHR^(b) S--, --CHR^(b) SCOCHR^(b) NR^(d) --, --CHR^(b) NR^(d)COCHR^(b) O--, --CHR^(b) NR^(d) COCHR^(b) S--, --CHR^(b) NR^(d)COCHR^(b) NR^(d) --, --CHR^(b) OCHR^(b) COO--, --CHR^(b) OCHR^(b) COS--,--CHR^(b) OCHR^(b) CONR^(d) --, --CHR^(b) SCHR^(b) COO--, --CHR^(b)SCHR^(b) COS--, --CHR^(b) SCHR^(b) CONR^(d) --, --CHR^(b) NR^(d) CHR^(b)COO--, --CHR^(b) NR^(d) CHR^(b) COS--, --CHR^(b) NR^(d) CHR^(b) CONR^(d)--, --OCO(CHR^(b))₂ O--, --OCO(CHR^(b))₂ S--, --OCO(CHR^(b))₂ NR^(d) --,--OCHR^(b) COCHR^(b) O--, -- OCHR^(b) COCHR^(b) S--, --OCHR^(b)COCHR^(b) NR^(d) --, --O(CHR^(b))₂ COO--, --O(CHR^(b))₂ COS--,--O(CHR^(b))₂ CONR^(d) --, --SCO(CHR^(b))₂ O--, --SCO(CHR^(b)) S--,--SCO(CHR^(b)) NR^(d) --, --SCHR^(b) COCHR^(b) O--, --SCHR^(b) COCHR^(b)S--, --SCHR^(b) COCHR^(b) NR^(d) --, --S(CHR^(b)) COO--, --S(CHR^(b))₂COS--, --S(CHR^(b))₂ CONR^(d) --, --NR^(d) CO(CHR^(b))₂ O--, --NR^(d)CO(CHR^(b))₂ S--, --NR^(d) CO(CHR^(b))₂ NR^(d) --, --NR^(d) CHR^(b)COCHR^(b) O--, --NR^(d) CHR^(b) COCHR^(b) S--, --NR^(d) CHR^(b)COCHR^(b) NR^(d) --, --NR^(d) (CHR^(b))₂ COO--, --NR^(d) (CHR^(b))₂COS--, --NR^(d) (CHR^(b))₂ CONR^(d) --, etc. In these formulae, R^(b),R^(c) and R^(d) are as defined above.

On the other hand, in the formula of the above (b), specific examples ofthe chained group formed by H, I, J, K and L include those representedby the following formulae: --(CHR^(f))₄ CHR^(i) --, --CR^(g) ═CR^(g)(CHR^(f))₂ CHR^(i) --, --CHR^(f) CR^(g) ═CR^(g) CHR^(f) CHR^(i) --,--(CHR^(f))₂ CR^(g) ═CR^(g) CHR^(i) --, --(CHR^(f))₃ CR^(g) ═CR^(j) --,--(CR^(g) ═CR^(g))₂ CHR^(i) --, --CHR^(f) CR^(g) ═CR ^(g) CR^(g) ═CR^(j)--, --CR^(g) ═CR^(g) CHR^(f) CR^(g) ═CR^(j) --, --O(CHR^(f))₃ CHR^(i--),--S(CHR^(f))₃ CHR^(i) --, --NR^(h) (CHR^(f))₃ CHR^(i) --, --CHR^(f)O(CHR^(f))₂ CHR^(i) --, --CHR^(f) S(CHR^(f))₂ CHR^(i) --, --CHR^(f)NR^(h) (CHR^(f))₂ CHR^(i) --, --(CHR^(f))₂ OCHR^(f) CHR^(i) --,--(CHR^(f))₂ SCHR^(f) CHR^(i) --, --(CHR^(f))₂ NR^(h) CHR^(f) CHR^(i)--, --(CHR^(f))₃ OCHR^(i) --, --(CHR^(f))₃ SCHR^(i) --, --(CHR^(f))₃NR^(h) CHR^(i) --, --O(CHR^(f))₂ OCHR^(i--), --O(CHR^(f))₂ SCHR^(i) --,--O(CHR^(f))₂ NR^(h) CHR^(i) --, --S(CHR^(f))₂ OCHR^(i) --,--S(CHR^(f))₂ SCHR^(i) --, --S(CHR^(f))₂ NR^(h) CHR^(i) --, --NR^(h)(CHR^(f))₂ OCHR^(i) --, --NR^(h) (CHR^(f))₂ SCHR^(i) --, --NR^(h)(CHR^(f))₂ NR^(h) CHR^(i) --, --CR^(g) ═CR^(g) COCHR^(f) CHR^(i) --,--(CR^(g) ═CR^(g))₂ CO--, --COCR^(g) ═CR^(g) CHR^(f) CHR^(i) --,--(CHR^(f))₂ CR^(g) ═CR^(g) CO--, --(CHR^(f))₂ COCR^(g) ═CR^(j) --,--CR^(g) ═CR^(g) COCR^(g) CR^(j) --, --OCHR^(f) CR^(g) CHR^(i) --,--OCOCR^(g) ═CR^(g) CHR^(i) --, --SCOCR^(g) ═CR^(g) CHR^(i) --, --NR^(h)COCR^(g) ═CR^(g) CHR^(i) --, --CHR^(f) OCHR^(f) CR^(g) ═CR^(j) --,--CHR^(f) SCHR^(f) CR^(g) ═CR^(j) --, --CHR^(f) NR^(h) CHR^(f) CR^(g)═CR^(j) --, --CR^(g) ═CR^(g) CHR^(f) OCHR^(i) --, --CR^(g) ═CR^(g)CHR^(f) SCHR^(i) --, --CR^(g) ═CR^(g) CHR^(f) NR^(h) CHR^(i) --,--O(CHR^(f))₂ CR^(g) ═CR^(j) --, --S(CHR^(f))₂ CR^(g) ═CR^(j) --,--NR^(h) (CHR^(f))₂ CR^(g) ═CR^(j) --, --COOCHR^(f) CR ^(g) ═CR.sup. j--, --COSCHR^(f) CR^(g) ═CR^(j) --, --CONR^(h) CHR^(f) CR^(g) ═CR^(j)--, --CR^(g) ═CR^(g) COOCHR^(i) --, --CR^(g) ═CR^(g) COSCHR^(i) --,--CR^(g) ═CR^(g) CONR^(h) CHR^(i) --, --CHR^(f) OCOCR^(g) ═CR ^(j) --,--CHR^(f) SCOCR^(g) ═CR^(j) --, --CHR^(f) NR^(h) COCR^(g) ═CR^(j) 13 ,--CR^(g) ═CR^(g) CHR^(f) OCO--, --CR^(g) ═CR^(g) CHR^(f) SCO--, --CR^(g)═CR^(g) CHR^(f) NR^(h) CO--, --OCOCHR^(f) OCHR^(i) --, --OCOCHR^(f)SCHR^(i) --, --OCOCHR^(f) NR^(h) CHR^(i) --, --SCOCHR^(f) OCHR^(i) --,--SCOCHR^(f) SCHR^(i) --, --SCOCHR^(f) NR^(h) CHR^(i) --, --NR^(h)COCHR^(f) OCHR^(i) --, --NR^(h) COCHR^(f) SCHR^(i) --, --NR^(h)COCHR^(f) NR^(h) CHR^(i) --, --OCOCHR^(f) OCO--, --OCOCHR^(f) SCO--,--OCOCHR^(f) NR^(h) CO--, --SCOCHR^(f) OCO--, --SCOCHR^(f) SCO--,--SCOCHR^(f) NR^(h) CO--, --NR^(h) COCHR^(f) OCO--, --NR^(h) COCHR^(f)SCO--, --NR^(h) COCHR^(f) NR^(h) CO--, --O(CHR^(f))₂ OCO--,--O(CHR^(f))₂ SCO--, --O(CHR^(f))₂ NR^(h) CO--, --S(CHR^(f))₂ OCO--,--S(CHR^(f))₂ SCO--, --S(CHR^(f))₂ NR^(h) CO-- , --NR^(h) (CHR^(f))₂OCO--, --NR^(h) (CHR^(f))₂ SCO--, --NR^(h) (CHR^(f))₂ NR^(h) CO--, etc.In these formulae, R^(f), R^(g), R^(h), R^(i) and R^(j) are as definedabove. Further, the aromatic ring represented by the above formula (i)or (ii) can be unsubstituted or monosubstituted by a halogen atom,hydroxyl group, cyano group, lower alkyl group or lower alkoxy group(see the definitions of R^(a) and R^(b)).

In the formula of the above (a), preferred as the aromatic ringrepresented by the above formula (i) is a benzene, furan, thiophene,oxazole, isoxazole, thiazole, isothiazole, 1,3,4-oxadiazole,1,3,4-thiadiazole, pyridine, pyridazine, pyrimidine or pyrazine ring,and preferred as the substituent R^(a) of the aromatic ring is ahydrogen atom, hydroxyl group, fluorine atom, chlorine atom, methylgroup, ethyl group or methoxy group. Further, preferred as the chainedgroup symbolized by the formula --C--D--E--F--G--is a group representedby the formula --(CH₂)₅ --, --CH(CH₃) (CH₂)₄ --, --CH═CH (CH₂)₃ --, --C(CH₃)═CH(CH₂)₃ --, --CH═C (CH₃) (CH₂)₃ --, --CH═CHCH (CH₃) (CH₂)₂ --,--(CH₂)₃ CH═CH--, --CH (CH₃)(CH₂)₂ CH═CH--, --(CH₂)₃ CH═C (CH₃)--,--(CH═CH)₂ CH₂ --, --C(CH₃)═ CHCH═CHCH₂ --, --CH═CHC(CH₃)═CHCH₂ --,--CH₂ (CH═CH)₂ --, --CH₂ CH═C(CH₃)CH═CH--, --CH═CHCH₂ CH═CH--, --S(CH₂)₄--, --CH₂ O(CH₂)₃ --, --CH(CH₃)O(CH₂)₃ --, --CH₂ OCH(CH₃)(CH₂)₂ --,--CH₂ S(CH₂)₃ --, --CH₂ NH(CH₂)₃ --, --CH₂ N(CH₃)(CH₂)₃ --, --(CH₂)₂O(CH₂)₂ --, --CH(CH₃)CH₂ O(CH₂)₂ --, --(CH₂)₂ S(CH₂)₂ --, --(CH₂)₂NH(CH₂ )₂ --, --(CH₂)₂ N(CH₃)(CH₂)₂ --, --(CH₂)₂ N(C₂ H₅) (CH₂)₂ --,--(CH₂)₃ OCH₂ --, --CH(CH₃)(CH₂)₂ OCH₂ --, --(CH₂)₃ SCH₂ --, --(CH₂)₃NHCH₂ --, --(CH₂)₃ N(CH₃)CH₂ --, --(CH₂)₄ O--, --CH(CH₃)(CH₂)₃ O--,--(CH₂)₄ S--, --(CH₂)₄ NH--, --(CH₂)₄ N(CH₃)--, --S(CH₂)₂ OCH₂ --,--NH(CH₂)₂ OCH₂ -- , --N(CH₃)(CH₂)₂ OCH₂ --, --CH₂ O(CH₂)₂ O--,--CH(CH₃)O(CH₂)₂ O--, --CH₂ OCH(CH₃) CH₂ O--, --CH₂ O(CH₂)₂ S--, --CH₂O(CH₂)₂ NH--, --CH₂ O(CH₂)₂ N (CH₃)--, --CH₂ S (CH₂)₂ O--, --CH₂NH(CH₂)₂ O--, --CH₂ N(CH₃)(CH₂)₂ O--, --S(CH₂)₃ O--, --NH(CH₂)₃ O--,--N(CH₃)(CH₂)₃ O--, --CO(CH₂)₄ --, --CH₂ CO (CH₂)₃ --, --(CH₂)₂ CO(CH₂)₂--, --(CH₂)₃ COCH₂ --, --(CH₂)₄ CO--, --COCH═CH(CH₂)₂ --, --COCH═C (CH₃)(CH₂)₂ --, --CO(CH═CH)₂ --, --COCH═C (CH₃) CH═ CH--, --CH═CHCO(CH₂)₂ --,--C(CH₃)═CHCO(CH₂)₂ --, --(CH₂)₂ COCH═CH--, --CH═CHCOCH═CH--, --C(CH₃)═CHCOCH═CH--, --(CH₂)₂ CH═CHCO--, --(CH═CH)₂ CO--, --C(CH₃)═CHCH═CHCO--,--NHCO(CH₂)₃ --, --N(CH₃)CO(CH₂)₃ --, --SCH₂ CO(CH₂)₂ --, --S(CH₂)₂COCH₂ --, --S(CH₂)₃ CO--, --SCH₂ CH═CHCO--, --S(CH₂)₂ CH═CH--,--NH(CH₂)₂ CH═CH--, --N(CH₃)(CH₂)₂ CH═CH--, --SCH₂ COCH═CH--,--COO(CH₂)₃ --, --CONH(CH₂)₃ --, --CON(CH₃)(CH₂)₃ --, --CH₂ OCO(CH₂)₂--, --CH₂ NHCO(CH₂)₂ --, --CH₂ N(CH₃)CO(CH₂)₂ --, --CH₂ OCH₂ COCH₂ --,--CH₂ SCH₂ COCH₂ --, --CH₂ NHCH₂ COCH₂ --, --CH₂ O(CH₂)₂ CO--, --CH₂S(CH₂)₂ CO--, --CH₂ NH(CH₂)₂ CO--, --CH₂ OCH₂ CH═CH--, --CH(CH₃)COCH₂CH═CH--, --CH₂ OCH(CH₃)CH═CH--, --CH₂ OCH₂ CH═C(CH₃)--,--CH(CH₃)OCH(CH₃)CH═CH--, --CH₂ SCH₂ CH═CH--, --CH(CH₃)SCH₂ CH═CH--,--CH₂ NHCH₂ CH═CH--, --CH(CH₃)NHCH₂ CH═CH--, --CH₂ N(CH₃)CH₂ CH═CH--,--CH(CH₃)N(CH₃)CH₂ CH═CH--, --COOCH₂ CH═CH--, --CONHCH₂ CH═CH--,--CON(CH₃)CH₂ CH═CH--, --CH₂ OCOCH═CH--, --CH₂ NHCOCH═CH--, --CH₂N(CH₃)COCH═CH--, --COCH₂ O(CH₂)₂ --, --COCH₂ NH(CH₂)₂ --, -- COCH₂N(CH₃)(CH₂)₂ --, --CH₂ COO(CH₂)₂ --, --CH₂ CONH(CH₂)₂ --, --CH₂CON(CH₃)(CH₂)₂ --, --(CH₂)₂ OCOCH₂ --, --(CH₂)₂ NHCOCH₂ --, --(CH₂)₂N(CH₃)COCH₂ --, --(CH₂) , --(CH₂)₂ NHCH₂ CO--, --(CH₂)₂ N(CH₃)CH₂ CO--,--CO(CH₂)₂ OCH₂ --, --CO(CH₂)₂ SCH₂ --, --CO(CH₂)₂ NHCH₂ --, --CO(CH₂)₂N(CH₃)CH₂ --, --CH₂ COCH₂ OCH₂ --, --CH₂ COCH₂ SCH₂ --, --CH₂ COCH₂NHCH₂ --, --CH₂ COCH₂ N(CH₃)CH₂ --, --(CH₂)₂ COOCH₂ --, --(CH₂)₂ CONHCH₂--, --(CH₂)₂ CON(CH₃)CH₂ --, --(CH₂)₃ OCO--, --(CH₂)₃ NHCO--, --(CH₂)₃N(CH₃)CO--, --CH═CHCH₂ OCH --, --C(CH₃)═CHCH₂ OCH₂ --, --CH═C(CH₃)CH₂OCH₂ --, --CH═CHCH(CH₃)OCH₂ --, --CH═CHCH₂ OCH(CH₃)--, --C(C₂ H₅)═CHCH₂OCH₂ --, --C(CH₃)═CHCH(CH₃)OCH --, --CH═CHCH₂ SCH₂ --, --C(CH₃)═CHCH₂SCH₂ --, --CH═CHCH₂ NHCH₂ --, --C(CH₃)═CHCH₂ NHCH₂ --, --CH═CHCH₂N(CH₃)CH₂ --, --C(CH₃)═CHCH₂ N(CH₃)CH₂ --, --CH═CHCOOCH₂ --,--CH═CHCONHCH₂ --, --CH═CHCON(CH₃)CH₂ --, --CH═CHCH₂ OCO--, --CH═CHCH₂NHCO--, --CH═CHCH₂ N(CH₃)CO--, --CO(CH₂)₃ O--, --CO(CH₂)₃ S--,--CO(CH₂)₃ NH--, --CO(CH₂)₃ N(CH₃)--, --CH₂ CO(CH₂)₂ O--, --CH₂ CO(CH₂)₂S--, --CH₂ CO(CH₂)₂ NH--, --CH₂ CO(CH₂)₂ N(CH₃)--, --(CH₂)₂ COCH₂ O--,--(CH₂)₂ COCH₂ NH--, --(CH₂)₂ COCH₂ N(CH₃)--, --(CH₂)₃ COO--, --(CH₂)₃CONH--, --(CH₂)₃ CON(CH₃)--, --CH═CH(CH₂)₂ O--, --C(CH₃)═CH(CH₂)₂ O--,--CH═CHCH(CH₃)CH₂ O--, --CH═CH(CH₂)₂ S--, --C(CH₃)═CH(CH₂)₂ S--,--CH═CH(CH₂)₂ NH--, --C(CH₃)═CH(CH₂)₂ NH--, --CH═CH(CH₂)₂ N(CH₃)--,--C(CH₃)═CH(CH₂)₂ N(CH₃)--, --CH═CHCOCH₂ O--, --C(CH₃)═CHCOCH₂ O--,--CH═CHCOCH₂ NH--, --CH═CHCOCH₂ N(CH₃)--, --COCH═CHCH₂ O--, --COCH═CHCH₂NH--, --COCH═CHCH₂ N(CH₃)--, --OCOCH₂ OCH₂ --, --NHCOCH₂ OCH₂ --,--N(CH₃)COCH₂ OCH₂ --, --COO(CH₂)₂ O--, --CONH(CH₂)₂ O--,--CON(CH₃)(CH₂)₂ O--, --CH₂ OCOCH₂ O--, --CH₂ NHCOCH₂ O--, --CH₂N(CH₃)COCH₂ O--, --CH₂ OCH₂ COO--, --CH₂ OCH₂ CONH--, --CH₂ OCH₂CON(CH₃)--, --SCH₂ COCH₂ O--, --NHCO(CH₂)₂ O--or --N(CH₃)CO(CH₂)₂ O--.

Particularly preferred examples of the group of the above (a) includethose represented by the following formulae: ##STR9## In the aboveformulae, X denotes an oxygen atom, sulfur atom or imino group, and A¹,B¹ and R^(a) are as defined above.

On the other hand, in the group of the above (b), preferred as thearomatic ring represented by the above formula (ii) is a benzene, furan,thiophene, pyridine, oxazole, isoxazole, thiazole or isothiazole ring,and preferred as the substituent R^(e) on the aromatic ring is ahydrogen atom, hydroxyl group, fluorine atom, chlorine atom, methylgroup, ethyl group or methoxy group. Further, preferably exemplified asthe chained group symbolized by the formula --H--I--J--K--L--is a grouprepresented by the formula: --(CH₂)₅ --, --(CH₂)₂ CH(CH₃)(CH₂)₂ --,--(CH₂)₃ CH(CH₃)CH₂ --, --(CH₂)₄ CH(CH₃)--, --CH═CH(CH₂)₃ --,--CH═CHCH═CHCH₂ --, --CH═CHCH═C(CH₃)CH₂ --, --CH═CHC(CH₃)═CHCH --, --(CH)₃ CH═CH--, --(CH₂)₃ CH═C(CH₃)--, --(CH₂)₃ C(CH₃)═CH--, --O(CH₂)₄ --, --O(CH₂)₂ CH(CH₃)CH₂ --, --S(CH₂)₄ --, --NH(CH₂)₄ --, --CH₂ O(CH₂ )₃ --,--CH₂ OCH₂ CH(CH₃)CH₂ --, --CH₂ S(CH₂)₃ --, --CH₂ NH(CH₂)₃ --, --CH₂N(CH₃)(CH₂)₃ --, --(CH₂)₂ O(CH₂)₂ --, --(CH₂)₂ OCH(CH₃) CH₂ --, --(CH₂)₂S(CH₂)₂ --, --(CH₂)₂ NH(CH₂)₂ --, --(CH₂)₂ N(CH₃) (CH₂)₂ --, --(CH₂)₃OCH₂ --, --(CH₂)₂ CH(CH₃)OCH₂ --, --(CH₂)₃ OCH(CH₃)--, --(CH₂)₃ SCH₂ --,--(CH₂)₃ NHCH₂ --, --(CH₂)₃ N(CH₃)CH₂ --, --O(CH₂)₂ OCH₂ --, --OCH₂CH(CH₃)OCH₂ --, --O(CH₂)₂ OCH(CH₃)--, --O(CH₂)₂ SCH₂ --, --O(CH₂)₂ NHCH₂--, --O(CH₂)₂ N(CH₃)CH₂ --, --S(CH₂)₂ OCH₂ --, --S(CH₂)₂ SCH₂ --,--S(CH₂)₂ NHCH₂ --, --S(CH₂)₂ N(CH₃)CH₂ --, --NH(CH₂)₂ OCH₂ --,--NH(CH₂)₂ SCH₂ --, --NH(CH₂)₂ NHCH₂ --, --NH(CH₂)₂ N(CH₃)CH₂ --,--CH═CHCO(CH₂)₂ --, --CH═CHCOCH(CH₃)CH₂ --, --CH═CHCH═CHCO--,--CH═CHCH═C(CH₃)CO--, --CH═CHC(CH₃)═CHCO--, --COCH═CH(CH₂)₂ --,--COCH═CHCH(CH₃)CH₂ --, --(CH₂)₂ CH═CHCO--, --(CH₂)₂ CH═C(CH₃)CO--,--(CH₂)₂ COCH═CH--, --(CH₂)₂ COCH═C(CH₃)--, --COCH═CHCH═CH--,--COCH═CHC(CH₃)═CH--, --CH═CHCOCH═CH--, --OCH₂ CH═CHCH₂ --,--OCOCH═CHCH₂ --, --SCH₂ CH═CHCH₂ --, --NHCH₂ CH═CHCH₂ --,--NHCOCH═CHCH₂ --, --CH₂ OCH₂ CH═CH--, --CH₂ OCH₂ C(CH₃)═CH--, --CH₂SCH₂ CH═CH--, --CH₂ SCH₂ C(CH₃)═CH--, --CH₂ NHCH₂ CH═CH--, --CH₂N(CH₃)CH₂ CH═CH--, --CH═CHCH₂ OCH₂ --, --CH═CHCH(CH₃)OCH₂ --, --CH═CHCH₂OCH(CH₃)--, --CH═CHCH₂ SCH₂ --, --CH═CHCH(CH₃)SCH₂ --, --CH═CHCH₂ NHCH₂--, --CH═CHCH(CH₃)NHCH₂ --, --CH═CHCH₂ N(CH₃)CH₂ --, --CH═CHCH₂ N(C₂H₅)CH₂ --, --CH═CHCH₂ NHCO--, --CH═CHCH₂ N(CH₃)CO--, --O(CH₂)₂ CH═CH--,--S(CH₂)₂ CH═CH--, --NH(CH₂)₂ CH═CH--, --COOCH₂ CH═CH--, --CONHCH₂CH═CH--, --CH═CHCOOCH₂ --, --CH═CHCOOCH(CH₃)--, --CH═CHCOSCH₂ --,--CH═CHCONHCH₂ --, --CH═CHCONHCH(CH₃)--, --CH═CHCON(CH₃)CH₂ --,--CH═CHCON(C₂ H₅)CH₂ --, --CH₂ OCOCH═CH--, --CH₂ OCOC(CH₃)═CH--, --CH₂NHCOCH═CH--, --CH₂ NHCOC(CH₃)═CH--, --CH₂ N(CH₃)COCH═CH--, --CH═CHCH₂OCO--, --CH═CHCH(CH₃)OCO--, --CH═CHCH₂ SCO--, --CH═CHCH₂ SCO--,--CH═CHCH₂ NHCO--, --CH═CHCH₂ N(CH₃)CO--, --CH═CHCH₂ N(C₂ H₅)CO--,--OCOCH₂ OCH₂ --, --OCOCH₂ SCH₂ --, --OCOCH₂ NHCH₂ --, --OCOCH₂N(CH₃)CH₂ --, --NHCOCH₂ OCH₂ --, --NHCOCH(CH₃)OCH₂ --, --NHCOCH₂ SCH₂--, --NHCOCH₂ NHCH₂ --, --NHCOCH₂ N(CH₃)CH₂ --, --OCOCH₂ OCO--, --OCOCH₂NHCO--, --OCOCH₂ N(CH₃)CO--, --NHCOCH₂ OCO--, --NHCOCH₂ NHCO--,--NHCOCH₂ N(CH₃)CO--, --O(CH₂)₂ OCO--, --O(CH₂)₂ NHCO--, --OCH₂CH(CH₃)NHCO--, --O(CH₂ )₂ N(CH₃)CO--, --S(CH₂)₂ OCO--, --S(CH₂)₂ NHCO--,--NH(CH₂)₂ NHCO--or --NH(CH₂)₂ N(CH₃)CO--.

Particularly preferred as the groups of the above (b) are thoserepresented by the following formulae ##STR10## In the above formulae, Yand Y' are the same or different and each denotes an oxygen atom, sulfuratom or imino group, and A², B² and R^(e) are as defined above

R¹ denotes a hydrogen atom, lower alkyl group, lower haloalkyl group,lower alkenyl group, lower alkynyl group or cycloalkyl group, and amongthem, preferred as the lower alkyl group is a methyl, ethyl or propylgroup, preferred as the lower haloalkyl group is a 2-fluoroethyl group,preferred as the lower alkenyl group is an alkyl group, preferred as thelower alkynyl group is a propargyl group, and preferred as thecycloalkyl group is a cyclopropyl group.

R², R³, R⁴ and R⁵ are the same or different and each denotes a hydrogenatom, halogen atom or lower alkyl group, or R² and R⁴ and/or R³ and R⁵combine to denote a single bond. Preferred as the lower alkyl group is amethyl or ethyl group, and preferred as the halogen atom is a fluorineatom or chlorine atom. Further, the case where R² and R⁴, and/or R³ andR⁵ denote a single bond means that the part represented by ##STR11## andthe double bond formed therein may be either of cis (Z) and trans (E),but trans (E) form is preferred in general. Particularly preferably, R²,R³, R⁴ and R⁵ are hydrogen atoms at the same time, or R² and R⁴, and/orR³ and R⁵ combine to form a single bond and the remainder of R², R³, R⁴and R⁵ are the same or different and each is a hydrogen or fluorineatom.

R⁶ and R⁷ are the same or different and each denotes a hydrogen atom,halogen atom or lower alkyl group, or R⁶ and R⁷ combine to denote asingle bond. In the above, preferred as the lower alkyl group is amethyl or ethyl group, and preferred as the halogen atom is a fluorineor chlorine atom. Further, specifically the case where R⁶ and R⁷ denotea single bond means that the part represented by ##STR12## denotes atriple bond (--C.tbd.C--). Particularly preferably, R⁶ and R⁷ arehydrogen atoms, or R⁶ and R⁷ combine to form a single bond.

R⁸ and R⁹ are the same or a different and each is a fluorine atom,trifluoromethyl group or lower alkyl group, or R⁸ and R⁹ combine todenote a group forming a cycloalkane together with the adjacent carbonatom. Among them, mentioned as particularly preferred groups are thecase where each of R⁸ and R⁹ denotes a fluorine atom, methyl group,ethyl group, propyl group or trifluoromethyl group, or R⁸ and R⁹ form acyclopropane ring together with the adjacent carbon atom (namely, thepart denoted by ##STR13## particularly preferred is the case where bothR⁸ and R⁹ are methyl groups

R¹⁰ denotes a hydrogen atom, fluorine atom, trifluoromethyl group,acetoxy group, lower alkyl group or lower alkoxy group. In the above,preferred as the lower alkyl group is a straight-chain lower alkyl grouphaving 1 to 4 carbon atoms such as, for example, a methyl, ethyl, propylor butyl group, and preferred as the lower alkoxy group is astraight-chain alkoxy group having 1 to 3 carbon atoms such as amethoxy, ethoxy or propoxy group. Particularly, preferred is a hydrogenatom, fluorine atom, trifluoromethyl group, acetoxy group, methyl group,ethyl group, propyl group, methoxy group, ethoxy group or propoxy group,and most preferred is a fluorine atom, methyl group, ethyl group,methoxy group or ethoxy group.

The substituted amine derivative of the above formula [I] can exist inthe form of an acid addition salt, and mentioned as such an acidaddition salt is an inorganic acid salt such as, for example,hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, perchlorateor phosphate; or an organic acid salt such as, for example,p-toluenesulfonate, benzenesulfonate, methanesulfonate, oxalate,succinate, tartrate, citrate, fumarate or maleate, and apharmaceutically acceptable nontoxic salt is particularly preferred.

Further, there is a case where stereoisomers such as diastereomers,geometrical isomers or optical isomers exist about the compounds of theformula [I] of the invention, according to the form of theirsubstituents, and the compounds of the formula [I] of the inventioninclude all these stereoisomers and their mixtures.

Compounds of the formula [I] of the invention can be prepared, forexample, according to the methods indicated in the following reactionequations 1 to 3. ##STR14## wherein Z denotes an eliminatable group, R¹¹denotes a lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl or lowerhaloalkyl group, and Q, R, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹ and R¹⁰are as defined above.

Specifically mentioned as an eliminable group symboled by Z is a halogenatom such as a chlorine, bromine or iodine atom, or an organicsulfonyloxy group such as a methanesulfonyloxy or p-toluenesulfonyloxygroup.

Any of the reactions represented by the above reaction equations is analkylation reaction for primary or secondary amines well known in thefield of organic synthesis chemistry, and a most universal method usablefor synthesis of almost all the compounds of the invention. According tothe invention, an objective compound of the above formula [I] or [I-b]can usually be prepared by reacting an amine represented by the generalformula [II], [V] or [I-a] with a corresponding alkylating agentrepresented by the general formula [III], [IV] or [VI] in an equimolaror a small excess amount of the latter preferably in the range of 1 to 2moles of the latter per mole of the amine in a solvent having no badinfluence on the reaction, for example in an aromatic hydrocarbon suchas benzene, toluene or xylene; an ether such as ethyl ether,tetrahydrofuran or dioxane; a halogenated hydrocarbon such as methylenechloride, chloroform or dichloroethane; an alcohol such as ethanol orisopropanol; an aprotic polar solvent such as acetonitrile ordimethylsulfoxide; or a mixture thereof.

As for conditions of the reactions indicated in the above reactionequations 1, 2 and 3, reaction temperature is generally in the range ofabout -70° C. to the boiling point of the solvent, preferably about -20°C. to about 150° C., and reaction time can be usually 5 minutes to 10days, preferably 1 to 24 hours. Further, in order to let these reactionsproceed smoothly, it is advantageous in general to carry out thereactions in the presence of a base, and the base usable there includes,for example, an alkali metal hydride such as sodium hydride, lithiumhydride or potassium hydride; an alkali or alkaline earth metalhydroxide such as sodium hydroxide, potassium hydroxide or calciumhydroxide; an alkali metal carbonate salt such as sodium carbonate,potassium carbonate or sodium bicarbonate; or an organic amine such astriethylamine or pyridine. The use amount of these bases is generally anequimolar or excess amount, preferably in the range of 1 to 5 timesmoles based on the starting compound of the formula [II], [V] or [I-a].

Compounds of the invention can also be prepared by utilizing thereactions disclosed in the following reaction equations 4 to 7.##STR15## wherein

Y¹ denotes an oxygen atom, sulfur atom or group represented by theformula --NR^(d) --and Y² denotes an oxygen atom, sulfur atom or grouprepresented by the formula --NR^(h) --, wherein R^(d) and R^(h) are asdefined above;

X¹ and X², and X³ and X⁴ denote, together respectively, the remaininggroups when any one of C, D, E, F and G is the above Y¹, wherein C, D,E, F and G are as defined above;

X⁵ and X⁶, and X⁷ and X⁸ denote, together respectively, the remaininggroups when any one of H, I, J, and K is the above Y², wherein H, I, Jand K are as defined above; and

A¹, A², B¹, B², L, R, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R^(a),R^(e) and Z are as defined above.

The methods indicated in the above reaction equations 4 to 7 are generalpreparation methods of compounds of the invention containing heteroatom(s) such as oxygen atom(s), sulfur atom(s) or nitrogen atom(s) inthe chain formed by C, D, E, F and G or by H, I, J and K in the aboveformula [I], namely compounds of the above formulae [I-d], [I-e] and[I-f]. These compounds can be classified into ethers, sulfides, amines,esters, thioesters and amides depending on the kind of the heteroatom(s) contained and the kind of the groups adjacent thereto, and theycan be prepared according to general preparation methods well known inthe field of organic synthetic chemistry in accordance with respectivecompounds.

Namely, in case of an ether, sulfide or amine which contains oxygenatom(s), sulfur atom(s) or nitrogen atom(s) as hetero atom(s) in thechain in the general formula [I-c], [I-d], [I-e] or [I-f] and whereinboth groups adjacent to the hetero atom(s) are formed by a grouprepresented by the formula --CHR^(b) --or by the formula --CHR^(f) --,wherein R^(b) and R^(f) are as defined above, provided that X¹ and X⁴,and X⁵ and X⁸ may be a single bond, respectively, it can be prepared byreacting a hydroxy derivative, mercapto derivative or amino derivativerepresented by the general formula [VII], [X], [XI] or [XIV] with acorresponding compound represented by the general formula [VIII], [IX],[XII] or [XIII], in a solvent having no bad influence on the reaction,either in an equimolar ratio or in small excess of either of thereactive components, preferably using 1 to 2 moles of a compound of theformula [VII], [IX], [XI] or [XIII] per mole of a compound of theformula [VIII], [X], [XII] or [XIV]. The reaction solution usable thereincludes an aromatic hydrocarbon such as benzene, toluene or xylene; anether such as ethyl ether, tetrahydrofuran or dioxane; a halogenatedhydrocarbon such as methylene chloride, chloroform or dischloroethane; aketone such as acetone; an ester such as ethyl acetate; an aprotic polarsolvent such as acetonitrile, dimethylformamide or dimethylsulfoxide; ora mixture thereof As for conditions of the reaction, reactiontemperature is generally in the range of about -70° C. to the boilingpoint of the solvent, preferably in the range of about -20° C. to about150° C., and reaction time can be usually 10 minutes to 48 hours,preferably 1 to 24 hours Further, in this reaction, it is advantageousto carry out the reaction in the presence of a base for smoothproceeding thereof, and the base usable there can be an alkali metalhydride such as sodium hydride, lithium hydride or potassium hydride; analkali metal or alkaline earth metal hydride such as sodium hydroxide,potassium hydroxide or calcium hydroxide; an alkali metal carbonate saltsuch as sodium carbonate, potassium carbonate or sodium bicarbonate; oran organic amine such as triethylamine or pyridine The use amount ofthese bases is generally equimolar or in an excess amount, preferably 1to 5 moles per mole of each starting compound

Further, when the compound of the formula [I-c], [I-d], [I-e] or [I-f]is the above ether, the compound can be prepared by reacting a hydroxyderivative represented by the general formula [VII], [X], [XI] or [XIV]with a compound represented by the general formula [VIII], [IX], [XII]or [XIII] wherein the eliminable group (Z) denotes a halogen atom suchas a chlorine, bromine or iodine atom in a solvent having no badinfluence in the presence of a silver salt such as silvertrifluoroacetate or silver carbonate. The use amounts of each startingcompound and the silver salt can be usually preferably equimolar, buteither one can be in an excess amount. The reaction temperature can begenerally in the range of about -20° C. to the boiling point of thesolvent, preferably in the range of about 0° C. to about 100° C., andthe reaction time can be usually 10 minutes to 48 hours, preferably 1 to24 hours.

On the other hand, the synthesis of an ester, thioester or amide whichcontains oxygen atom(s), sulfur atom(s) or nitrogen atom(s) as heteroatom(s) in the chain in the general formula [I-c], [I-d], [I-e] or [I-f]and wherein one group adjacent to the hetero atom is a carbonyl groupand the other group is a group represented by the formula --CHR^(b) --orby the formula --CHR^(f) --wherein R^(b) and R^(f) are as defined above,provided that X¹ and X⁴, and X⁵ and X⁸ may be a single bond,respectively, can easily be carried out, too, by a general syntheticmethod of an ester thioester or amide well known in the field of organicchemistry. For example, such a compound can usually be prepared byreacting a hydroxy derivative, mercapto derivative or amino derivativewith a corresponding reactive derivative of a carboxylic acid such as anacid chloride or acid anhydride represented by the general formula[VIII], [IX], [XII] or [XIII], in an equimolar amount or in a smallexcess of one reactive component, preferably using 1 to 2 moles of thecompound of the formula [VII], [IX], [XI] or [XIII] per mole of thecompound of the formula [VIII], [X], [XII] or [XIV], in a solvent notinvolved in the reaction, for example in an organic solvent such astetrahydrofuran, dichloromethane, chloroform, benzene, ethyl acetate,acetone, acetonitrile, dimethylformamide or dimethylsulfoxide or a mixedsolvent thereof with water.

As for reaction conditions therefor, reaction temperature is generallyin the range of about -70° C. to the boiling point of the solvent,preferably in the range of about -20° C. to about 100° C., and reactiontime can be usually 5 minutes to 10 days, preferably 10 minutes to 24hours. Further, for smooth progress of the reaction it is advantageousto carry out the reaction in the presence of a base, and the base usablethere includes, for example, an alkali metal or alkaline earth metalhydroxide such as sodium hydroxide, potassium hydroxide or calciumhydroxide; an alkali metal carbonate salt such as sodium carbonate,potassium carbonate or sodium bicarbonate; or an organic amine such astriethylamine or pyridine. The use amount of these bases is generallyequimolar or excess, preferably 1 to 5 moles per mole of each startingcompound.

Further, some of the compounds of the invention can also be preparedaccording to the methods indicated in the following reaction equations 8to 11. ##STR16## wherein

X⁹ and X¹⁰, and X¹¹ and X¹² denote, together respectively, the remaininggroups when any neighboring two of the previously defined C, D, E, F andG combine to form a group represented by the formula --CH₂ NH--or agroup represented by the formula --NHCH₂ --;

X¹³ and X¹⁴, and X¹⁵ and X¹⁶ denote, together respectively, theremaining groups when any neighboring two of the previously defined H,I, J and K combine to form a group represented by the formula --CH₂NH--or by a group represented by the formula --NHCH₂ --; and

A¹, A², B¹, B², L, R, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R^(a)and R^(e) are as defined above.

The methods indicated in the above reaction equations 8 to 11 arepreparation methods for compounds of the invention having a grouprepresented by --CH₂ NH--or a group represented by --NHCH --in the chainformed by C, D, E, F and G or by H, I, J, K and L, namely compounds ofthe above formulae [I-g], [I-h], [I-i] and [I-j]. The reactionsindicated by the above reaction equations 8 to 11 can, for example, becarried out by previously condensing a compound of the formula [XV],[XVIII], [XIX] or [XXII] with an almost equimolar amount of a compoundof the formula [XVI], [XVII], [XX] or [XXI] in benzene, tetrahydrofuranor an alcohol to form an imine and reducing it. Mentioned as thereducing agent usable for this reduction is, for example, a complexmetal hydride such as sodium borohydride, sodium cyanoborohydride orlithium aluminum hydride. Further, as reduction conditions therefor,there is, for example, a method which comprises carrying out thereaction in a solvent such as methanol, ethanol or tetrahydrofuran atabout 0° C. to room temperature for 1 to 6 hours using a reducing agentin an equimolar or excess mole amount based on the imine, preferablyusing 1 to 5 moles thereof per mole of the imine.

Some compounds of the invention can further be prepared even by themethods indicated by the following reaction equations 12 to 15.##STR17## wherein

M denotes a group represented by the formula: ##STR18## wherein Gdenotes a halogen atom, or by the formula: ##STR19## wherein R^(i)denotes a lower alkyl group;

X¹⁷ and X¹⁸, and X¹⁹ and denote, together respectively, the remaininggroups when any neighboring two of the previously defined C, D, E, F andG combine to form a double bond optionally substituted by a lower alkylgroup;

X²¹ and X²², and X²³ and denote, together respectively, the remaininggroups when any neighboring two of the previously defined H, I, J, K andL combine to form a double bond optionally substituted by a lower alkylgroup; and

A¹, A², B¹, B², L, R, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R^(a),R^(c), R^(e), R^(g) and R^(i) are as defined above.

The reactions indicated in the above reaction equations 12 to 15 aregeneral preparation methods for compounds of the invention having doublebond(s) in the chain formed by C, D, E, F and G or by H, I, J, K and L,namely for the compound of the above formula [I-k], [I-1], [I-m] and[I-n]. Namely, such a compound can be prepared by reacting a phosphoniumsalt or phosphonate represented by the general formula [XXIII], [XXVI],[XXVII] or [XXX] with an aldehyde or ketone represented by the generalformula [XXIV], [XXV], [XXVIII] or [XXIX] in an equimolar ratio or in arate of small excess of the latter in a solvent having no relation tothe reaction. As the solvent to be used there, in case of, for example,a phosphonium salt derivative tetrahydrofuran, dimethylformamide or thelike is preferred, and in case of a phosphonate derivativetetrahydrofuran, benzene, toluene or the like is preferred. Further,this reaction is preferably carried out usually in the presence of abase, and especially when a phosphonium salt derivative is used as astarting compound, it is necessary to let a base act in advance or inthe reaction system. Such a base can, for example, include sodiumhydroxide, sodium hydride, butyllithium or the like. Although thereaction conditions largely vary depending on the reaction seeds to beused, reaction temperature and reaction time are, for example, about-70° C. to about 200° C. and about 10 minutes to about 24 hours,respectively.

Because of diversity in the structure of compounds of the invention, itis also possible to synthesize them via various routes according toother various preparation methods well known in organic syntheticchemistry, in addition to the various preparation methods exemplifiedabove. These preparation methods include, for example, construction of aheterocyclic group in the final step, e.g. a method indicated by thefollowing reaction equation: ##STR20## , and construction of an en-yneor diyne structure similarly in the final step, e.g. methods indicatedby the following reaction equations 17 to 19: ##STR21##

In each of the above-described reaction methods, when in addition to thehydroxyl group, mercapto group or amino group having relation to thereaction, a reactive functional group such as a hydroxyl group or aminogroup coexists in the compounds to be used as starting compounds, it ispossible, if necessary, to carry out the reaction after appropriateprotection of these reactive functional groups and remove theseprotective groups after the reaction. Protective groups to be used thereinclude those readily eliminated by hydrolysis under an acidic oralkaline condition, for example, methoxymethyl, tetrahydropyranyl,trityl, dimethyl(tert butyl)silyl, formyl, acetyl, methoxycarbonyl,ethoxycarbonyl and tertbutoxycarbonyl groups.

Compounds of the formula [I] of the invention to be obtained by theabove steps can be isolated and purified, for example, by columnchromatography, solvent extraction, recrystallization or the like, aloneor in appropriate combinations. Further, if necessary, compounds of theinvention of the formula [I] as a free base can be converted to theiracid addition salts, or reversely, their acid addition salts can beconverted to their free bases The step to convert compounds of theformula [I] as a free base to their acid addition salts, or the step toconvert acid addition salts to their free bases can easily be carriedout by a conventional method using a corresponding acid or base,respectively

Starting compounds of the formulae [II] to [XXX] used in the abovereaction equations 1 to 15 can either be purchased as a commercialproduct, or prepared by the methods disclosed in Japanese Laid-OpenPatent Publication No. 5059/1988, the methods previously reported by thepresent inventors [see Japanese Patent Application No. 296840/1988,EP-A-318860, WO 90/5132 (PCT/JP89/00522)] or methods based thereon, orfurther methods disclosed in the later reference examples or othermethods.

Compounds of the invention of the formula [I] inhibit mammal squaleneepoxidase extremely selectively and strongly, and are thus usefulcompounds whose use is expected as an antihypercholesterolemia agent, anantihyperlipemia agent or an antiarteriosclerosis agent.

In order to verify this, a test example is mentioned and describedbelow. Test example

Squalene epoxidase inhibition action

(1) Preparation of squalene epoxidase

Human squalene epoxidase is prepared based on the method disclosed in J.Biol. Chem. 245, 1670 (1970) and ibid. 250, 1572 (1975).

Namely, human hepatoma (Hep-G2) cells are cultured at 37° C. under 5%carbon dioxide-mixed air. After completion of the culture the cells arescraped and recovered by centrifugation. The cells are suspended (1 ×10⁸cells/ml) in a 0.1M Tris-HCl buffer (pH 7.5), the suspension ishomogenized and centrifuged at 9,750×g for 10 minutes, and the sedimentis washed with a 0.1M Tris-HCl buffer (pH 7.5) and centrifuged at105,000×g for 1 hour. The resulting microsome is suspended in a 0.1MTris-HCl buffer (pH 7.5) so that the protein amount becomes 20 mg/ml,and the suspension is stirred under ice cooling in the presence of 1 %Triton X-100 for solubilization. After this solubilization treatment,the solution is diluted with 1 mM EDTA and 1 mM dithiothreitol so thatthe Triton X-100 concentration becomes 0.125 %, and then centrifuged at105,000×g for 1 hour. The resulting supernatant is used in the latertest as a squalene epoxidase fraction.

(2) Method for measurement of squalene epoxidase activity

Measurement of human squalene epoxidase activity is carried out based onthe method disclosed in J. Biol. Chem. 245, 1670 (1970).

Namely, 3 Ml of a dimethylsulfoxide solution of a test drug is added toa solution consisting of 0.2 ml of the squalene epoxidase fractionprepared in (1) [Protein amount 0.4 mg, 0.1 % Triton X-100, 20 μMTris-HCl buffer (pH 7.5)], 100 μM FAD, 1 mM NADPH, 1 mM EDTA totalvolume 0.3 ml, and the mixture is subjected to shaking reaction at 37°C. for 60 minutes. 0.3 ml of a 10 % potassium hydroxide-methanolsolution is added to stop the reaction, and the mixture is heated at 75°C. for 1 hour. Then, after extraction of the nonsaponified substances,the extract is concentrated to dryness in a stream of nitrogen. Theresulting residue is dissolved in a small amount of ethyl ether, droppedon Pre-coated silicagel TLC and developed with benzene-ethyl acetate(99.5:0.5). The position of the formed ³ H-squalene-2,3-epoxide on TLCis ascertained using as a marker ergosterol acetate and the ³H-squalene-2,3-epoxide part of TLC is cut out. The TLC piece is immersedin a toluene series scintillator and measurement is carried out using aliquid scintillation counter. By this, 50% inhibitory concentrations(IC50 values) of compounds of the invention on squalene epoxidase aredetermined, and the results are shown in the following table.

                  TABLE 1                                                         ______________________________________                                        Human squalene epoxidase                                                      inhibition action                                                                              50% inhibitory                                               Test drug        concentration (IC50, nM)                                     ______________________________________                                        Compound of Example 7                                                                          0.3                                                          Compound of Example 30                                                                         0.8                                                          Compound of Example 35                                                                         0.4                                                          Compound of Example 38                                                                         0.2                                                          Compound of Example 46                                                                         0.4                                                          Compound of Example 48                                                                         0.5                                                          ______________________________________                                    

As apparent from the above results, compounds of the invention areeffective for treatment or prophylaxis of various diseases caused bysthenia of the cholesterol biosynthesis mechanism and/or excessiveingestion of cholesterol, etc., for example, diseases such as obesity,hypercholesterolemia, hyperlipemia and arteriosclerosis. Further, thesqualene epoxidase inhibition action of compounds of the invention isnot observed on fungi, etc. and is specific for mammals and theirtoxicity is low, and thus the, invention is extremely useful in thefield of medicine

Compounds of the formula [I] of the invention can be administered orallyor parenterally, and can be provided, through formulation into formssuitable for such administrations, for treatment and prophylaxis ofhypercholesterolemia, hyperlipemia, arteriosclerosis, etc. In case wherecompounds of the invention are clinically used, it is also possible toadminister them after they are variously formulated in accordance withtheir administration forms and in addition of pharmaceuticallyacceptable additives. Additives usable therefor include variousadditives usually used in the pharmaceutical filed, for example,gelatin, lactose, sucrose, titanium oxide, starch, crystallinecellulose, hydroxypropylcellulose, carboxymethylcellulose, corn starch,microcrystalline wax, white Vaseline, magnesium metasilicate aluminate,anhydrous calcium phosphate, citric acid, trisodium citrate,hydroxypropylcellulose, sorbitol, sorbitan aliphatic acid esters,polysorbate, sucrose aliphatic acid esters, polyoxyethylenecured castoroil, polyvinylpyrrolidone, magnesium stearate, light anhydrous silicicacid, talc, vegetable oils, benzyl alcohol, gum arabic, propyleneglycol, polyalkylene glycol, cyclodextrin, hydroxypropylcyclodextrin,etc. Dosage forms into which compounds of the invention formulated as amixture with these additives include solid formulations such as, forexample, tablets, capsuls, granules, powders and suppository; and liquidformulations such as, for example, syrups, elixirs and injections, andthese can be prepared according to usual methods in the filed offormulations. The liquid formulations may be in the form wherein theyare dissolved or suspended in a suitable medium at the time of use.Further, particularly in case of injections, they can be dissolved orsuspended, if necessary, in physiological saline or a glucose solution,and a buffering agent and a preservative can also be added.

These formulations can contain a compound of the invention in the rateof 0 to 100 weight %, preferably 1.0 to 60 weight %. These formulationcan also contain another therapeutically effective compound

When a compound of the invention is used as an antihyperlipemia agent,an antiarteriosclerosis agent or an antihypercholesterolemia agent, itsdose and the number of administration vary depending on the sex, age,body weight and the severity of symptom of patients and the type andrange of the intended therapeutic effect and the like. Generally, inoral administration, it is administered preferably in a daily dose of0.01 to 20 mg per kg of an adult once or in several divided portions Inparenteral administration, it is preferably administered in a daily doseof 0.001 to 2 mg per kg of an adult once or in several divided portions

EXAMPLE 1 Production of(E,E)-N-ethyl-N-(6,6-dimethyl-2-hepten-4-ynyl)-3-[3-(3-thienyl)-2-propenyloxymethyl]benzylaminehydrochloride

6.9 g of (E)-3-[3-(3-thienyl)-2-propenyloxymethyl]benzyl bromide wasdissolved in 50 ml of dimethylformamide, and 5.3 g of(E)-N-ethyl-6,6-di-methyl-2-hepten-4-ynylamine hydrochloride and 7.0 gof potassium carbonate were added. The solution was stirred overnight atroom temperature. The solvent was evaporated, and ethyl acetate andwater were added to the residue to extract it. The organic layer wasseparated, washed with a saturated aqueous solution of sodium chloride,and dried over anhydrous magnesium s sulfate. The desiccant wasseparated by filtration, and the solvent was evaporated under reducedpressure The residue was dissolved in 10 ml of ethanol, and to thissolution, a hydrogen chloride-methanol solution was added, then thesolvent was evaporated again The residue was recrystallized from amixture of ethyl ether and hexane to give 6.7 g (yield 72 %) of thecaptioned compound as a white powder, m.p.103°-105° C.

IR(KBr,cm⁻¹) 3448,2968,2926,2608,1458,1398,1110,966,771 ¹ H-NMR(300MHz,CDCl₃,δppm):1.24(9H,s),1.44(2H,t,J=7.1Hz),1.54-1.57(2H,m),2.94-3.05(2H,m),3.52-3.57(1H,m),3.65-3.67(1H,m),4.08-4.13(2H,m),4.20(2H,dd,J=6.5Hz,1.4Hz),4.59(2H,s),5.82(1H,d,J=15.9Hz),6.17(1H,dt,J=15.9Hz,6.5Hz),6.26(1H,dt,J=15.6Hz,7.3Hz),6.65(1H,d,J=15.6Hz),7.17-7.23(2H,m),7.26-7.28(1H,m),7.44(2H,d,J=4.7Hz),7.61-7.64(2H,m).

Compounds of Examples 2 to 7 were obtained by s performing the samereaction as in Example 1 except that the corresponding bromomethyl orchloromethyl derivatives and/or 2-hepten-4-ynylamine derivatives wereused instead of the starting compounds,(E)-3-[3--(3-thienyl)-2-propenyloxymethyl]benzyl bromide and/or (E)-N-ethyl-6,6-dimethyl-2-hepten-4-ynylamine hydrochloride, which were usedin the above-mentioned reaction. ( When the reaction product was a freebase, the hydrochloride producing step in the after-treatment was notincluded.)

EXAMPLE 2(E,E)-N-ethyl-N-(6,6-dimethyl-2-hepten-4-ynyl)-3-[3-(3-thienylmethoxy)-1-propenyl]benzylamine

IR(neat,cm⁻¹): 2968,2866,1458,1365,1266,1107,1083,966, 774,693.

¹ H-NMR(300MHz,CDCl₃,δppm):1.04(3H,t,J=7.0Hz),1.24(9H,s),2.50(2H,q,J=7.0Hz),3.09(2H,dd,J=6.3Hz,1.4Hz),3.54(2H,s),4.18(2H,dd,J=6.4Hz,1.6Hz),4.58(2H,s),5.64(1H,dt,J=15.9Hz,1.4Hz),6.08(1H,dt,J=15.9Hz,6.3Hz),6.31(1H,dt,J═15.8Hz,6.4Hz),6.62(1H,dt,J=15.8Hz,1.6Hz),7.10-7.12(1H,m),7.20-7.27(4H,m),7.30-7.33(1H,m),7.35(1H, br.s).

EXAMPLE 3 (E)-N-ethyl-N-(6,6-dimethyl-2-hepten-4-ynyl)-3-[3-(3-thienyl)propoxymethyl]benzylamine

IR(neat,cm⁻¹) 2968,2926,1455,1365,1266,1152,1107,960, 774.

¹ H-NMR(300 MHz,CDCl₃,δ ppm):1.04(3H,t,J=7.1 Hz),1.24(9H,s),1.92-1.97(2H,m),2.50(2H,q,J=7.1 Hz),2.75(2H,t,J=7.7Hz),3.09(2H,dd,J=6.3 Hz,1.5 Hz),3.50(2H,t,J=6.5 Hz),3.56(2H,s),4.49(2H,s),5.64(1H,dt,J=15.9 Hz,1.5 Hz),6.07 (1H,dt,J=15.9Hz,6.3 Hz),6.90-6.95(2H,m),7.20-7.30(5H,m).

EXAMPLE 4(E,E)-N-ethyl-(6,6-dimethyl-2-hepten-4-ynyl)-3-[3-(5-thiazolyl)-2-propenyloxymethyl]benzylamine

IR(neat,cm⁻¹): 2974,1458,1365,1266,1113,960,870.

¹ H-NMR(300 MHz,CDCl₃,δ ppm):1.04(3H,t,J=7.1 Hz),1.23(9H,s),2.50(2H,q,J=7.1 Hz),3.09(2H,dd,J=6.6 Hz,1.5 Hz),3.56(2H,s),4.16(2H,dd,J=5.5 Hz,1.5 Hz),4.56(2H,s),5.64(1H, dt,J=15.9Hz,1.5Hz),6.07(1H,dt,J=15.9 Hz,6.6 Hz),6.18(1H, dt,J=15.9 Hz,6.0Hz),6.80(1H,d,J=15.9 Hz),7.22-7.31(4H, m),7.74(1H,s),8.63(1H,s).

EXAMPLE 5(E)-N-ethyl-N-(6,6-dimethyl-2-hepten-4-ynyl)-3-2-[2-(3-thienyl)ethoxy]ethyl]benzylamine

IR(neat,cm⁻¹): 2968,2866,1707,1365,1113,774.

¹ MHz,CDCl₃,δ ppm):1.04(3H,t,J=7.1 Hz),1.23(9H, s),2.50(2H,q,J=7.1Hz),2.88(2H,t,J=6.8 Hz),2.90(2H,t,J=6.1 Hz),3.08(2H,dd,J=6.3 Hz,1.5Hz),3.53(2H,s),3.62-3.71 (4H,m),5.64(1H,dt,J=15.9 Hz,1.5Hz),6.07(1H,dt,J=15.9 Hz, 6.3Hz),6.92-6.98(2H,m),7.07(1H,dt,J=7.2Hz,1.5Hz),7.14- 7.29(4H,m).

EXAMPLE 6(E,E)-N-(6,6-dimethyl-2-hepten-4-ynyl)-N-propyl-3-3-(3-thienyl)-2-propenyloxymethyl]benzylaminehydrochloride

m.p.: 70°-72° C.

IR(KBr,cm⁻): 3442,2974,2932,1458,1110,969.

¹ H-NMR(300 MHz,CDCl₃,δ ppm):0.94(3H,t,J=7.4 Hz),1.25(9H,s),1.90-1.94(2H,m),2.80-2.87(2H,m),3.55-3.68(2H,m),4.11-4.15(2H,m),4.20(2H,dd,J=6.8 Hz,1.3 Hz),4.59(2H,s), 5.82(1H,d,J=16.0Hz),6.17,6.25(1H,dt,J=16.0 Hz,6.8 Hz), 6.66(1H,d,J=16.0Hz),7.18(1H,dd,J=3.1 Hz,1.3 Hz),7.22(1H, dd,J=5.1 Hz,1.2Hz),7.27(1H,dd,J=5.1 Hz,3.1 Hz),7.44-7.46 (2H,m),7.60-7.63(2H,m).

EXAMPLE 7(E,E)-N-ethyl-N-(6-methoxy-6-methyl-2-hepten-4-ynyl)-3-[3-(3-thienyl)-2-propenyloxymethyl]benzylaminehydrochloride

m.p.:100°-102° C.

IR(KBr,cm⁻¹): 2614,2584,1170,1122,1077,966.

¹ H-NMR(300 MHz,CDCl₃,δ ppm):1.46(3H,t,J=7.2 Hz),1.48(6H,s),2.90-3.16(2H,m),3.36(3H,s),3.48-3.78(2H,m),4.05-4.20(2H,m),4.20(2H,dd,J=6.5Hz,1.5 Hz),4.59(2H,s),5.87 (1H,d,J=15.9 Hz),6.17(1H,dt,J=15.9 Hz,6.3Hz),6.40(1H,dt, J=15.9 Hz,6.5 Hz),6.65(1H,d,J=15.9 Hz),7.17-7.30(3H,m),7.43-7.50(2H,m),7.59-7.68(2H,m).

EXAMPLE 8 (E,E)-N-ethyl-N-(6-methoxy-6-methyl-2-hepten-4-ynyl)-5-[3-(3-thienyl)-2-propenyloxymethyl]-1,2,4-oxadiazol-2-ylmethylamine

IR(KBr,cm⁻¹): 2980,2938,1362,1248,1173,1149,1113,1074, 966,771.

¹ H-NMR(300 MHz,CDCl₃,δ ppm):1.09(3H,t,J=7.0 Hz),1.46(6H,s),2.59(2H,q,J=7.0 Hz),3.25(2H,dd,J=6.5 Hz,1.4 Hz),3.35(3H,s),3.81(2H,s),4.29(2H,dd,J=6.6 Hz,1.2 Hz),4.76(2H,s),5.72(1H,dt,J=15.9 Hz,1.4 Hz),6.13(1H,dt,J=15.9 Hz, 6.5Hz),6.16(1H,dt,J=15.9 Hz,6.6 Hz),6.66(1H,d,J=15.9 Hz),7.18-7.23(2H,m),7.26-7.30(1H,m).

EXAMPLE 9(E,E)-N-ethyl-N-(6-methoxy-6-methyl-2-hepten-4-ynyl)-6-[3-(3-thienyl)-2-propenyloxymethyl]-2-pyridylmethylamine

IR(KBr,cm⁻¹): 2980,1461,1248,1173,1149,1116,1077,966,768.

¹ H-NMR(300 MHz,CDCl₃,δ ppm):1.05(3H,t,J=7.1 Hz),1.46(6H,s),2.56(2H,q,J=7.1 Hz),3.17(2H,dd,J=6.3 Hz,1.7 Hz),3.35(3H,s),3.72(2H,s),4.25(2H,dd,J=6.3 Hz,1.7 Hz),4.66(2H,s),5.70(1H,dt,J=16.1 Hz,1.7 Hz),6.17(1H,dt,J=16.1 Hz, 6.3Hz),6.19(1H,dt,J=16.1 Hz,6.3 Hz),6.66(1H,dt,J=16.1 Hz, 1.7Hz),7.16(1H,dd,J=2.5 Hz,1.2 Hz),7.21(1H,dd,J=5.2 Hz, 1.2Hz),7.27(1H,dd,J=5.2 Hz,2.5 Hz),7.33(1H,d,J=7.7 Hz), 7.39(1H,d,J=7.7Hz),7.67(1H,t,J=7.7 Hz).

EXAMPLE 10 Production of(E)-N-ethyl-N-(6-methoxy-6-methyl-2-hepten-4-ynyl)-2-2-[3-(3-thienyl)phenoxy]ethoxy]ethylaminehydrochloride

12.0 g of 3-[3-[2-(2-chloroethoxy)ethoxy]phenyl] thiophene, 11.1 g of(E)-N-ethyl-6-methoxy-6-methyl-2-hepten-4-ynylamine hydrochloride, 17.6g of potassium carbonate and 7.0 g of potassium iodide were dissolved in300 ml of dimethylformamide, and the mixture was stirred at 95° to 105 °C. for 5 hours. The solvent was evaporated under reduced pressure, andethyl acetate and water were added to the residue to extract it. Theorganic layer was separated, washed with a saturated aqueous solution ofsodium chloride, and dried over anhydrous magnesium sulfate. Thedesiccant was separated by filtration, and the solvent was evaporatedunder reduced pressure. The residue was purified by silica gel columnchromatography [hexane/ethyl acetate=5/1→2/1→1/2] to give 15.7 g (yield88.6 %) of the captioned free base as a pale yellow oil. The free base(15.7 g) obtained as above was dissolved in methanol, treated with ahydrogen chloride-methanol slution and recrystallized from ethyl etherto give 15.4 g (yield 87.2%) of the captioned compound as a whitecrystalline powder, m.p.103°-105° C.

IR(KBr,cm⁻¹): 3450,2932,2620,1599,1464,1449,1221,1128, 1074,777.

¹ H-NMR(300 MHz,CDCl₃,δ ppm): 1.41(3H,t,J=6.7 Hz),1.44(6H,s),3.12-3.28(4H,m),3.31(3H,s),3.76-3.86(2H,m),3.88-3.91(2H,m),4.00-4.14(2H,m),4.14-4.20(2H,m),5.90(1H,d,J=15.9 Hz),6.25-6.40(1H,m),6.86(1H,ddd,J=8.1 Hz,2.7 Hz, 2.1Hz),7.12(1H,t,J=2.2 Hz),7.21(1H,ddd,J=8.4 Hz,2.7 Hz, 2.1Hz),7.31(1H,t,J=7.8 Hz),7.35-7.40(2H,m),7.45(1H,dd, J=2.7 Hz,1.2 Hz).

Compounds of Examples 11 to 20 were obtained by performing the samereaction as in Example 10 except that the corresponding chloroalkyl orbromoalkyl derivatives and/or alkynylamine derivatives were used insteadof the starting compounds,3-[3-[2-(2-chloroethoxy)ethoxy]phenyl]thiophene and/or(E)-N-ethyl-6-methoxy-6-methyl-2-hepten-4-ynylamine, which were used inthe above-mentioned reaction.

EXAMPLE 11(E)-N-(6,6-dimethyl-2-hepten-4-ynyl)-3-2-[3-(3-thienyl)phenyl]ethoxypropylamine

IR(neat,cm⁻¹): 2968,1458,1364,1266,1114,960,774.

¹ H-NMR(300 MHz,CDCl₃,δ ppm):1.00(3H,t,J=7.2 Hz),1.23(9H,s),1.73(1H,q,J=6.6 Hz),2.45-2.59(4H,m),2.92(2H,t,J=7.2Hz),3.12(2H,d,J=6.6 Hz),3.48(2H,t,J=6.6 Hz),3.65(2H, t,J=7.2Hz),5.52(1H,dt,J=15.9 Hz,1.5 Hz),6.03(1H,dt,J=15.9 Hz,6.6Hz),7.15(1H,dt,J=7.2 Hz,1.8 Hz),7.32(1H,dt,J=7.5 Hz,1.5Hz),7.37-7.39(2H,m),7.42-7.48(3H,m).

EXAMPLE 12(E)-N-ethyl-N-(6,6-dimethyl-2-hepten-4-ynyl)-5-[3-(3-thienyl)phenoxy]pentylaminehydrochloride

m.p.:119°-121° C.

IR(KBr,cm⁻¹): 3432,2972,2944,2872,2616,2488,1602,1480,1456,1286,1270,1222,1186,776.

¹ H-NMR(300 MHz,CDCl₃,δ ppm):1.24(9H,s),1.41(3H,t,J=7.2Hz),1.50-2.00(6H,m),2.90-3.00(2H,m),3.08(2H,q,J=7.2 Hz),3.65(2H,d,J=7.2Hz),4.02(2H,t,J=6.0 Hz),5.85(1H,d,J=15.9 Hz),6.17(1H,dt,J=15.9 Hz,7.2Hz),6.82(1H,ddd,J=8.1 Hz,2.1 Hz,1.5 Hz),7.11(1H,br.t,J=2.1Hz),7.18(1H,dt,J=8.1 Hz,1.5 Hz),7.30(1H,t,J=8.1 Hz),7.37(2H,d,J=2.4 Hz),7.45(1H,t,J=2.4 Hz).

EXAMPLE 13(E)-N-ethyl-N-(6-methoxy-6-methyl-2-hepten-4-ynyl)-5-[3-(3-thienyl)phenoxy]pentylamine

IR(neat,cm⁻¹): 3442,2986,2938,2614,2500,1605,1584,1473,1455,1365,1287,1248,1221,1173,1152,1071, 966,777.

¹ H-NMR(300 MHz,CDCl₃,δ ppm):1.42(3H,t,J=7.2 Hz),1.47(6H,s),1.50-2.00(6H,m),2.92-3.20(2H,m),3.10(2H,q,J=7.2 Hz),3.34(3H,s),3.67(2H,d,J=7.2 Hz),4.03(2H,t,J=6.0 Hz),5.91 (1H,d,J=15.9Hz),6.32(1H,dt,J=15.9 Hz,7.2 Hz),6.82(1H, ddd,J=8.1 Hz,2.7 Hz,1.2Hz),7.11(1H,br.t,J=2.4 Hz),7.19 (1H,d,J=8.1 Hz),7.30(1H,t,J=8.1Hz),7.37(2H,d,J=2.4 Hz), 7.45(1H,t,J=2.4 Hz).

EXAMPLE 14(E,E)-N-ethyl-N-(6,6-dimethyl-2-hepten-4-ynyl)-6-3-(3thienyl)phenyl]-5-hexenylamine

IR(neat,cm⁻¹): 2974,2932,1600,1461,1365,1269,1203,1086, 963,849,771.

¹ H-NMR(300 MHz,CDCl₃,δ ppm):1.01(3H,t,J=7.2 Hz),1.24(9H,s),1.48-1.50(4H,m),2.24(2H,q,J=6.3 Hz),2.44(2H,t,J=7.2Hz),2.51(2H,q,J=7.2 Hz),3.11(2H,dd,J=6.3 Hz,1.5 Hz), 5.63(1H,dt,J=15.9Hz,1.5 Hz),6.05(1H,dt,J=15.9 Hz,6.3 Hz), 6.27(1H,dt,J=15.9 Hz,6.3Hz),6.42(1H,d,J=15.9 Hz),7.22-7.50(6H,m),7.55(1H,br.s).

EXAMPLE 15(E)-N-ethyl-N-(6,6-dimethyl-2-hepten-4-ynyl)-2-[2-[3-(5-thiazolyl)phenoxy]ethoxy]ethylamine

IR(neat,cm⁻¹): 2968,1602,1581,1479,1443,1278,1128,1056, 870.

¹ H-NMR(300 MHz,CDCl₃,δ ppm):1.03(3H,t,J=7.2 Hz),1.23(9H,s),2.59(2H,q,J=7.2 Hz),2.71(2H,t,J=6.0 Hz),3.20(2H,d,J=6.3Hz),3.65(2H,t,J=6.0 Hz),3.83(2H,t,J=4.9 Hz),4.16(2H, t,J=4.9Hz),5.63(1H,dt,J=15.9 Hz,1.5 Hz),6.05(1H,dt,J=15.9 Hz,6.3Hz),6.90(1H,ddd,J=8.1 Hz,2.7 Hz,2.7 Hz),7.14 (1H,dd,J=2.7 Hz,1.8Hz,),7.17(1H,ddd,J=8.1 Hz,1.8 Hz,1.8 Hz),7.32(1H,t,J=8.1Hz),8.07(1H,s),8.74(1H,s).

EXAMPLE 16(E)-N-ethyl-N-(6,6-dimethyl-2-hepten-4-ynyl)-2-[2-[3-(3-pyridyl)phenoxy]ethoxy]ethylamine

IR(neat,cm⁻¹): 2968,1605,1476,1302,1218,1128,1056,783.

¹ H-NMR(300 MHz,CDCl₃,δ ppm):1.03(3H,t,J=7.1 Hz),1.23(9H,s),2.58(2H,q,J=7.1 Hz),2.71(2H,t,J=6.0 Hz),3.20(2H,d,J=6.3Hz),3.65(2H,t,J=6.0 Hz),3.84(2H,t,J=4.8 Hz),4.18(2H, t,J=4.8Hz),5.62(1H,dt,J=15.9 Hz,1.3 Hz),6.05(1H,dt,J=15.9 Hz,6.3Hz),6.96(1H,ddd,J=8.4 Hz,2.4 Hz,2.4 Hz),7.13 (1H,dd,J=2.4 Hz,1.8Hz),7.16(1H,ddd,J=7.5 Hz,2.4 Hz,1.8 Hz),7.35(1H,ddd,J=8.2 Hz,5.1 Hz,1.0Hz),7.38(1H,t,J=8.1 Hz),7.86(1H,ddd,J=8.2 Hz,2.6 Hz,1.8Hz),8.59(1H,dd,J= 5.0 Hz,1.8 Hz),8.34(1H,d,J=2.7 Hz,1.0 Hz).

EXAMPLE 17(E)-N-ethyl-N-(6,6-dimethyl-2-hepten-4-ynyl)-2-[2-[3-(1-imidazolyl)phenoxy]ethoxy]ethylamine

IR(neat,cm⁻¹): 2968,1611,1509,1215,1128,1056.

¹ H-NMR(300 MHz,CDCl₃,δ ppm):1.02(3H,t,J=7.5 Hz),1.23(9H,s),2.56(2H,q,J=7.5 Hz),2.68(2H,t,J=6.0 Hz),3.17(2H,dd,J=6.6 Hz,1.5Hz,),3.63(2H,t,J=6.0 Hz),3.83(2H,t,J=6.0 Hz), 4.16(2H,t,J=6.0Hz),5.64(1H,dt,J=15.6 Hz,1.5 Hz),6.03(1H, dt,J=15.6 Hz,6.6Hz),6.91(1H,ddd,J=8.4 Hz,2.4 Hz,1.2 Hz), 6.94-6.99(2H,m),7.19(1H,t,J=1.2Hz),7.27(1H,t,J=1.2 Hz), 7.36(1H,ddd,J=8.4 Hz,8.2 Hz,0.6Hz),7.84(1H,t,J=1.2 Hz).

EXAMPLE 18(E)-N-(6-ethoxy-6-methyl-2-hepten-4-ynyl)-N-propyl-5-[3-(3-thienyl)phenoxy]pentylaminehydrochloride

m.p.:62°-64° C.

IR(KBr,cm⁻¹): 2980,2938,2878,1605,1584,1455,1290,1221,1188,1161,1068,966,777.

¹ H-NMR(300 MHz,CDCl₃,δ ppm):1.00(3H,t,J=7.3 Hz),1.20(3H,t, J=6.8Hz),1.47(6H,s),1.50-1.70(4H,m),1.80-2.00(6H,m),2.70-3.00(4H,m),3.57(2H,q,J=7.3 Hz),3.66(2H,d,J=7.6 Hz), 4.02(2H,t,J=6.0Hz),5.88(1H,d,J=15.5 Hz),6.29(1H,dt,J=15.5 Hz,7.6 Hz),6.81(1H,ddd,J=8.0Hz,2.8 Hz,0.9 Hz),7.11 (1H,dd,J=2.8 Hz,1.8 Hz),7.18(1H,ddd,J=7.5 Hz,1.8Hz,0.9 Hz),7.30(1H,dd,J=8.0 Hz,7.5 Hz),7.36-7.40(2H,m),7.45(1H, dd,J=2.7Hz,2.0 Hz).

EXAMPLE 19(E)-N-(6-ethoxy-6-methyl-2-hepten-4-ynyl)-N-propyl-2-[2-[3-(3-thienyl)phenoxy]ethoxy]ethylaminehydrochloride

m.p.:110°-111° C.

IR(KBr,cm⁻¹): 2986,2932,2632,1602,1452,1245,1224,1134, 1065,966,777.

¹ H-NMR(300 MHz,CDCl₃,δ ppm):0.96(3H,t,J=7.2 Hz),1.18(3H,t, J=7.2Hz),1.45(6H,s),1.82-1.90(2H,m),2.96-3.02(2H,m), 3.22(2H,t,J=4.5Hz),3.54(2H,q,J=7.2 Hz),3.79(2H,d,J=7.3Hz),3.87-3.90(2H,m),4.09-4.10(2H,m),4.16-4.20(2H, m),5.89(1H,d,J=15.9Hz),6.29(1H,dt,J=15.9 Hz,7.3 Hz), 6.83(1H,ddd,J=8.0 Hz,2.3 Hz,0.9Hz),7.13(1H,dd,J=2.3 Hz, 1.8 Hz),7.21(1H,ddd,J=7.8 Hz,1.8 Hz,0.9Hz),7.31(1H,dd,J=8.0 Hz,7.8 Hz),7.37(1H,dd,J=4.9 Hz,1.3Hz),7.38(1H,dd,J=4.9 Hz,2.6 Hz),7.45(1H,dd,J=2.6 Hz,1.3 Hz).

EXAMPLE 20 N-ethyl-N-(6,6-dimethyl-2,4-heptadiynyl)-2-[2-[3-(3-thienyl)phenoxy]ethoxy]ethylamine

IR(neat,cm-⁻¹): 2974,1605,1455,1287,1128,1059.

¹ H-NMR (300 MHz,CDCl₃,δ ppm):1.06(3H,t,J=7.0 Hz),1.24(9H,s),2.60(2H,q,J=7.0 Hz),2.76(2H,t,J=5.7 Hz),3.55(2H,s), 3.67(2H,t,J=5.7Hz),3.84(2H,t,J=5.0 Hz),4.18(2H,t,J=5.0 Hz),6.85(1H,ddd,J=7.8 Hz,2.3Hz,1.0 Hz),7.14-7.22(2H, m),7.30(1H,t,J=7.8 Hz),7.37(2H,d,J=2.2Hz),7.44(1H,t,J=2.2 Hz).

EXAMPLE 21 Production of(E,E)-N-ethyl-N-(6,6-dimethyl-2-hepten-4-ynyl)-5-[3-(3-thienyl)phenoxy)-2-pentenylamine

90 mg of 5-[3-(3-thienyl)phenoxy]-2-penten-1-ol was dissolved in 3 ml ofethyl acetate, and 69 μl of triethylamine and 34 μl of methanesulfonylchloride were added with ice cooling and stirring. The solution wasstirred for 30 minutes, and then water and ethyl acetate were added. Theorganic layer was separated, washed with a saturated aqueous solution ofsodium chloride, and dried over anhydrous magnesium sulfate. Thedesiccant was separated by filtration, and the solvent was evaporatedunder reduced pressure. The residue was dissolved in 2 ml ofdimethylformamide, and 101 mg of(E)-N-ethyl-6,6-dimethyl-2-hepten-4-ynylamine hydrochloride, 69 mg ofpotassium carbonate and 83 mg of potassium iodide were added. Themixture was stirred s overnight at room temperature, and then ethylether and water were added. The organic layer was separated, washed witha saturated aqueous solution of sodium chloride, and dried overanhydrous magnesium sulfate. The desiccant was separated by filtration,and the solvent was evaporated under reduced pressure. The residue waspurified by medium-pressure liquid chromatography [silica gel column,hexane/ethyl acetate=15/1→15/2]]to give 68 mg (yield 49%) of thecaptioned compound as a colorless oil.

IR(neat,cm⁻¹): 2968,1605,1584,1455,1287,1221,1128,1059, 774.

¹ H-NMR(300 MHz,CDCl₃,δ ppm):1.02(3H,t,J=7.1 Hz),1.23(9H,s),2.50(2H,q,J=7.1 Hz),2.45-2.60(2H,m),3.08(2H,d,J=5.1Hz),3.10(2H,d,J=6.5 Hz),4.04(2H,t,J=7.0Hz),5.56-5.74(3H,m),6.04(1H,dd,J=15.9 Hz,6.6 Hz),6.83(1H,ddd,J=8.4Hz,3.0 Hz,2.1 Hz),7.12(1H,dd,J=3.0 Hz,2.1 Hz),7.17(1H, ddd,J=7.5 Hz,3.0Hz,2.1 Hz),7.29(1H,t,J=7.8 Hz),7.37(2H,d, J=2.1 Hz),7.44(1H,t,J=2.1 Hz).

Compounds of Examples 22 and 23 were obtained by performing the samereaction as in Example 21 except that(E)-4-[3-(3-thienyl)benzyloxy]-2-buten-1-ol and/or the corresponding2-hepten-4-ynylamine derivative were used instead of the startingcompounds, (E)-5-[3-(3-thienyl)phenoxy]-2-penten-1-ol, which were usedin the above-mentioned reaction.

EXAMPLE 22(E,E)-N-ethyl-N-(6-methoxy-6-methyl-2-hepten-4-ynyl)-4-[3-(3-thienyl)benzyloxy]-2-butenylamine

IR(neat,cm 2980,2938,1173,1149,1074,774.

¹ H-NMR(300 MHz,CDCl₃,δ ppm):1.03(3H,t,J=7.0 Hz),1.46(6H,s),2.51(2H,q,J=7.0 Hz),3.10(2H,dd,J=4.0 Hz,1.3 Hz),3.13 (2H,dd,J=6.6Hz,1.4 Hz),3.35(3H,s),4.04(2H,dd,J=3.4 Hz, 1.4Hz),4.55(2H,s),5.66(1H,dt,J=15.8 Hz,1.4Hz),5.75-5.78(2H,m),6.13(1H,dt,J=15.8 Hz,6.6 Hz),7.24-7.28(1H,m),7.34-7.41(3H,m),7.46(1H,dd,J=2.8 Hz,1.7 Hz),7.51(1H,dt, J=7.8 Hz,1.2Hz),7.56-7.58(1H,m).

EXAMPLE 23(E,E)-N-ethyl-N-(6,6-dimethyl-2-hepten-4-ynyl)-4-[3-(3-thienyl)benzyloxy]-2-butenylamine

IR(neat,cm⁻¹): 2974,2932,1365,1107,774.

¹ H-NMR(300 MHz,CDCl₃,δ ppm):1.03(3H,t,J=7.1 Hz),1.24(9H,s),2.53(2H,q,J=7.1 Hz),3.04-3.20(4H,m),4.03-4.06(2H,m),4.55(2H,s),5.63(1H,dt,J=15.9 Hz,1.5 Hz),5.75-5.80(2H,m),6.04(1H,dt,J=15.9 Hz,6.6 Hz),7.24-7.42(4H,m),7.46(1H,dd, J=2.7 Hz,1.7Hz),7.52(1H,dt,J=7.3 Hz,1.6 Hz),7.56-7.59(1H, m).

EXAMPLE 24 Production of(E)-N-ethyl-N-(6,6-dimethyl-2-hepten-4-ynyl)-5-[3-(3-thienyl)phenoxy]-4-oxopentylamine

50 mg of 5-bromo-1-[3-(3-thienyl)phenoxy]-2-pentanone was dissolved in1.8 ml of dimethylformamide, and 125 mg of a(E)-N-ethyl-6,6-dimethyl-2-hepten-4-ynylamine hydrochloride and 29 mg ofpotassium iodide were added. The mixture was stirred at 40° C. for 1hour, and then ethyl ether and ice water were added. The organic layerwas separated, washed with a saturated aqueous solution of sodiumchloride, and dried over anhydrous magnesium sulfate. The desiccant wasseparated by filtration, and the solvent was evaporated under reducedpressure. The residue was purified by silica gel column chromatography[hexane→chloroform] to give 20 mg (yield 27%) of the captioned compoundas a colorless oil.

IR(neat,cm⁻¹): 2968,2926,1728,1605,1584,1458,1218,774.

¹ H-NMR(300 MHz,CDCl₃,δ ppm):0.97(3H,t,J=7.1 Hz),1.23(9H,s),1.79(2H,q,J=7.1 Hz),2.42(2H,t,J=7.1 Hz),2.48(2H,q,J= 7.1Hz),2.62(2H,t,J=7.1 Hz),3.07(2H,dd,J=6.6 Hz,1.5 Hz),4.62(2H,s),5.60(1H,dt,J=14.5 Hz,1.5 Hz),6.00(1H,dt,J=14.5 Hz,6.6Hz),6.80(1H,dd,J=7.1 Hz,2.8 Hz),7.14(1H,t,J=1.6 Hz),7.23(1H,dt,J=7.8Hz,1.2 Hz),7.29(1H,t,J=10.5 Hz), 7.35-7.40(2H,m),7.45(1H,dd,J=2.6 Hz,1.4Hz).

EXAMPLE 25 Production of(E,E)-N-ethyl-N-(6,6-dimethyl-2-hepten-4-ynyl)-2-[3-[3-(3-thienyl)phenyl]-2-propenyloxy]ethylaminehydrochloride

3.7 g of (E)-2-[3-[3-(3-thienyl)phenyl]-2-propenyloxy]ethanol wasdissolved in 100 ml of ethyl acetate, and 1.4 ml of methanesulfonylchloride and 4.0 ml of triethylamine were added under ice cooling. Themixture was stirred for 30 minutes, and then the precipitate was removedby filtration. The solvent was evaporated under reduced pressure and theresidue was dissolved in 100 ml of dimethylformamide. 4.3g of(E)-N-ethyl-6,6-dimethyl-2-hepten-4-ynylamine hydrochloride, 2.6 g ofpotassium iodide and 3.9 g of potassium carbonate were added, themixture was heated at 90° C. for 4 hours. The solvent was evaporatedunder reduced pressure, and ethyl acetate and water were added to theresidue to extract it. The organic layer was separated, washed with asaturated aqueous solution of sodium s chloride, and dried overanhydrous magnesium sulfate. The desiccant was separated by filtration,and the solvent was evaporated under reduced pressure. The residue waspurified by silica gel column chromatography [hexane/ethyl acetate=2/1]to give 4.5 g (yield 76%) of free base of the captioned compound as apale yellow oil.

The resulting free base (4.5 g) was dissolved in methanol, treated witha hydrogen chloride-methanol solution and recrystallized from ethylether to give 3.9 g of the captioned compound as a white crystallinepowder, 133°-134° C.

IR(KBr,cm⁻¹): 2968,2866,2566,2470,1461,1365,1266,1137, 978,771.

¹ H-NMR(300 MHz,CDCl₃,δ ppm):1.23(9H,s),1.44(3H,t,J=7.5Hz),3.10-3.30(4H,m),3.78-3.82(2H,m),3.95-4.15(2H,m), 4.21(2H,d,J=6.3Hz),5.89(1H,d,J=15.6 Hz),6.21(1H,dt,J=15.6 Hz,7.5 Hz),6.30(1H,dt,J=15.9Hz,6.3 Hz),6.65(1H,d,J=15.9 Hz),7.30-7.36(2H,m),7.39(2H,d,J=2.1Hz),7.46-7.51 (2H,m),7.59-7.61(1H,m).

Compounds of Examples 26 to 29 were obtained by performing the samereaction as in Example 25 except that the corresponding alcoholderivatives and/or 2-hepten-4-ynylamine derivatives were used instead ofthe starting compounds,(E)-2-[3-[3-(3-thienyl)phenyl]-2propenyloxy]ethanol and/or(E)-N-ethyl-6,6-dimethyl-2-hepten-4-ynylamine hydrochloride, which wereused in the above-mentioned reaction.

EXAMPLE 26 (E,E)-N-ethyl-N-(6,6-dimethyl-2-hepten-4-ynyl)-2-[3-[4-(3-thienyl)-2-thienyl]-2-propenyloxy]ethylamine

IR(neat,cm⁻¹): 2968,1458,1365,1266,1203,1107,957,837, 783,750.

¹ H-NMR(300 MHz,CDCl₃,δ ppm):1.04(3H,t,J=7.2 Hz),1.23(9H,s),2.59(2H,q,J=7.2 Hz),2.70(2H,t,J=6.0 Hz),3.19(2H,dd,J=6.6 Hz,1.5Hz),3.57(2H,t,J=6.0 Hz),4.12(2H,dd,J=6.0 Hz, 1.5 Hz),5.64(1H,dt,J=15.9Hz,1.5 Hz),6.06(1H,dt,J=15.9 Hz, 6.6 Hz),6.15(1H,dt,J=15.9 Hz,6.0Hz),6.72(1H,dt,J=15.9 Hz, 1.5 Hz),7.16-7.20(2H,m),7.27-7.35(3H,m).

EXAMPLE 27(E)-N-ethyl-N-(6,6-dimethyl-2-hepten-4-ynyl)-2-[2-[3-(3-thienyl)phenoxy]ethoxy]ethylaminehydrochloride m.p.:79° C.

IR(KBr,cm⁻¹): 3442,2968,2578,2482,1602,1452,1287,1122, 777.

¹ H-NMR(300 MHz,CDCl₃,δ ppm):1.27(9H,s),1.04(3H,t,J=6.7Hz),3.10-3.30(4H,m),3.76-3.80(2H,m),3.88-3.90(2H,m),4.07-4.10(1H,m),4.13-4.19(3H,m),5.85(1H,d,J=15.8 Hz), 6.17(1H,dt,J=15.8Hz,7.3 Hz),6.83(1H,ddd,J=8.1 Hz,2.7 Hz, 2.4 Hz),7.13(1H,t,J=2.4Hz),7.21(1H,dt,J=6.9 Hz,1.8 Hz), 7.31(1H,t,J=8.1Hz),7.35-7.40(2H,m),7.45(1H,dd,J=3.3 Hz, 1.2 Hz).

EXAMPLE 20(E)-N-ethyl-N-(6-methoxy-6-methyl-2-hepten-4-ynyl)-2-1-methyl-2-[3-(3-thienyl)phenoxy]ethoxy]ethylamine

IR(neat,cm⁻¹): 2980,2932,1605,1452,1287,1221,1173,1152, 1074,771.

¹ H-NMR(300 MHz,CDCl₃,δ ppm):1.02(3H,t,J=7.0 Hz),1.29(3H,d, J=6.0Hz),1.45(6H,s),2.57(2H,q,J=7.0 Hz),2.68(2H,t,J=6.0 Hz),3.20(2H,dd,J=6.4Hz,1.6 Hz),3.34(3H,s),3.65(1H, dt,J=12.0 Hz,6.0 Hz),3.68(1H,dt,J=12.0Hz,6.0 Hz),3.80-3.89(1H,m),3.91(1H,dt,J=15.9 Hz,1.6Hz),6.15(1H,dt,J=15.9 Hz,6.4 Hz),6.84(1H,ddd,J=8.0 Hz,2.8 Hz,1.0Hz),7.14 (1H,dd,J=2.5 Hz,2.4 Hz),7.19(1H,ddd,J=7.5 Hz,1.8 Hz,0.9Hz),7.30(1H,t,J=7.9 Hz),7.36-7.38(2H,m),7.44(1H,t,J=2.0 Hz).

EXAMPLE 29(E)-N-ethyl-N-(6-methoxy-6-methyl-2-hepten-4-ynyl)-2-2-[3-(3-thienyl)phenoxy1ethoxy]propylamine

IR(neat,cm⁻¹): 2980,2932,1605,1584,1452,1287,1221,1173,1149,1122,1074,771.

¹ H-NMR(300 MHz,CDCl₃,δ ppm):1.01(3H,t,J=7.3 Hz),1.19(3H,d, J=6.1Hz),1.45(6H,s),2.39(1H,dd,J=13.4 Hz,5.4 Hz),2.60 (1H,dd,J=13.4 Hz,6.4Hz),2.49-2.61(2H,m),3.17(1H,ddd,J=15.0 Hz,6.8 Hz,1.4Hz),3.22(1H,ddd,J=15.0 Hz,6.8 Hz,1.4 Hz),3.34(3H,s),3.58-3.69(1H,m),3.83(1H,dt,J=10.7 Hz,5.3 Hz),3.89(1H,dt,J=10.7 Hz,5.3 Hz),4.15(2H,t,J=5.3 Hz),5.67(1H, dt,J=15.8Hz,1.4 Hz),6.15(1H,dt,J=15.8 Hz,6.8 Hz),6.85(1H, ddd,J=8.5 Hz,2.9 Hz,1.3Hz),7.15(1H,dd,J=2.2 Hz,1.7 Hz), 7.18(1H,ddd,J=7.5 Hz,1.4 Hz,1.2Hz),7.29(1H,t,J=7.5 Hz), 7.37(2H,m),7.44(1H,dd,J=2.4 Hz,2.0 Hz).

EXAMPLE 30 Production of (E,E)-N-ethyl-N-(6-methoxy-6-methyl-2-hepten-4-ynyl)-5-[3-(3-thienyl)-2-propenyloxymethyl]-2-furylmethylaminehydrochloride

18.0 g of(E)-N-ethyl-5-[3-(3-thienyl)-2-propenyloxymethyl]-2-furylmethylamine wasdissolved in 400 ml of dimethylformamide, and 13.0 g of(E)-6-methoxy-6-methyl-2-hepten-4-ynyl bromide (contaminated with about5 wt % of the (Z)-isomer) and 18.0 g of potassium carbonate were added.The mixture was stirred at room temperature for 24 hours, and then ethylether and water were added. The organic layer was separated, washed witha saturated aqueous solution of sodium chloride, and dried overanhydrous magnesium sulfate. The desiccant was separated by filtration,and the solvent was evaporated under reduced pressure. The residue waspurified by silica gel column chromatography [hexane/ethylacetate=8/1→2/1] to give 21.8 g of free base of the captioned compoundas a colorless oil.

The resulting free base was dissolved in 240 ml of ethyl ether, and toits solution was added, dropwise with stirring, 65 ml of a 0.5M hydrogenchloride-ethyl ether solution with stirring to give 22.3 g (yield 81%)of the captioned compound as a white crystalline powder, m.p. 91°-92.5°C.

IR(KBr,cm⁻¹): 2980,2914,2674,2608,1170,1098,1068,1056, 969,804.

¹ H-NMR(300 MHz,CDCl₃,δ ppm):1.47(6H,s),1.51(3H,t,J=7.2Hz),2.94-3.06(2H,m),3.34(3H,s),3.58-3.60(2H,m),4.17 (2H,dd,J=1.4 Hz,7.0Hz),4.23(2H,br.s),4.48(2H,s),5.92 (1H,d,J=15.9 Hz),6.11(1H,dt,J=15.9Hz,6.2 Hz),6.40(1H,d, J=3.2 Hz),6.45(1H,dt,J=15.9 Hz,7.0Hz),6.62(1H,d,J=15.9 Hz),6.67(1H,d,J=3.2 Hz),7.18(1H,d,J=3.0Hz),7.20(1H,dd, J=5.2 Hz,1.2 Hz),7.28(1H,dd,J=5.2 Hz,3.0 Hz).

Compounds of Examples 31 to 44 were obtained by performing the samereaction as in Example 30 except that the corresponding aminederivatives and/or alkynyl bromide derivatives were used instead of thestarting compounds,(E)-N-ethyl-5-[3-(3-thienyl)-2-propenyloxymethyl]-2-furylmethylamineand/or (E)-6-methoxy-6-methyl-2-hepten-4-ynyl bromide, which were usedin the above-mentioned reaction.

EXAMPLE 31(E)-N-(2-fluoroethyl)-N-(6,6-dimethyl-2-hepten-4-ynyl)-2-[2-[3-(3-thienyl)phenoxy]ethoxy]ethylaminehydrochloride

m.p. 109°-111° C.

IR(KBr,cm⁻¹): 2974,2596,2530,1599,1452,1284,1272,1221,1131,1092,1062,960,840,774.

¹ H-NMR(300 MHz,CDCl₃,δ ppm):1.22(9H,s),3.34-3.60(4H,m),3.84-3.89(4H,m),4.10-4.19(4H,m),4.97(2H,d,J=47.6 Hz), 5.87(1H,d,J=15.9Hz),6.22(1H,dt,J=15.9 Hz,7.6 Hz),6.83 (1H,ddd,J=8.0 Hz,2.3 Hz,1.0Hz),7.13(1H,dd,J=2.3 Hz,1.5 Hz),7.21(1H,ddd,J=7.8 Hz,1.5 Hz,1.0Hz),7.31(1H,dd,J=8.0 Hz,7.8 Hz),7.37(1H,dd,J=5.1 Hz,1.7Hz),7.38(1H,dd,J=5.1 Hz,2.7 Hz),7.46(1H,dd,J=2.7 Hz,1.7 Hz).

EXAMPLE 32(E)-N-cyclopropyl-N-(6,6-dimethyl-2-hepten-4-ynyl)-2-[2-[3-(3-thienyl)phenoxy]ethoxy]ethylaminehydrochloride

m.p. 86°-88° C.

IR(KBr,cm⁻¹): 3450,2974,2560,1596,1452,1221,1131,1089, 1062,777.

¹ H-NMR(300 MHz,CDCl₃,δ ppm):0.78-0.85(4H,m),1.22(9H,s),2.40-2.60(1H,m),3.24-3.27(2H,m),3.65-4.30(4H,m),3.87 (2H,t,J=4.8Hz),4.19(2H,t,J=4.8 Hz),5.86(1H,d,J=16.2 Hz), 6.19(1H,dt,J=16.2 Hz,7.2Hz),6.82-6.86(1H,m),7.13(H,t,J=1.8 Hz),7.31(1H,t,J=7.8 Hz).

EXAMPLE 33(E)-N-ethyl-N-(6,6-dimethyl-2-hepten-4-ynyl)-2-[2-[3-(3-thienyl)phenoxy]ethylthio]ethylamine

IR(neat,cm⁻¹) 2974,1605,1584,1455,1287,1218,1182,771.

¹ H-NMR(300 MHz,CDCl₃,δ ppm):1.03(3H,t,J=7.1 Hz),1.23(9H,s),2.55(2H,q,J=7.1 Hz),2.71(4H,s),2.94(2H,t,J=6.5 Hz), 3.14(2H,dd,J=6.3Hz,1.5 Hz),4.19(2H,t,J=6.9 Hz),5.64(1H, dt,J=15.9 Hz,1.5Hz),6.04(1H,dt,J=15.9 Hz,6.3 Hz),6.84(1H, dd,J=8.1 Hz,2.7Hz),7.13(1H,t,J=2.1 Hz),7.20(1H,dd,J=7.8 Hz,1.8 Hz),7.31(1H,t,J=7.8Hz),7.35(2H,d,J=2.7 Hz), 7.45(1H,dd,J=2.1 Hz,2.1 Hz).

EXAMPLE 34(E)-N-cyclopropyl-N-(6-ethoxy-6-methyl-2-hepten-4-ynyl)-2-[2-[3-(3-thienyl)phenoxy]ethoxy]ethylaminehydrochloride

m.p.:118°-120° C.

IR(KBr,cm⁻¹): 2566,1602,1449,1248,1224,1164,1128,1071, 981,777.

¹ H-NMR(300 MHz,CDCl₃,δ ppm):0.81-0.98(2H,m),1.18(3H,t,J=7.2Hz),1.44(6H,s),1.72-1.89(2H,m),2.49-2.60(1H,m),3.32-3.40(2H,m),3.53(2H,q,J=7.2 Hz),3.78-3.90(3H,m),3.90-4.09(2H,m),4.11-4.30(3H,m),5.93(1H,d,J=15.8 Hz), 6.31(1H,dt,J=15.8Hz,7.8 Hz),6.82(1H,ddd,J=8.0 Hz,2.3 Hz, 1.4 Hz),7.12(1H,dd,J=2.3 Hz,1.7Hz),7.21(1H,ddd,J=8.0 Hz, 1.7 Hz,1.4 Hz),7.31(1H,dd,J=8.1 Hz,8.0Hz),7.37(1H,dd,J=5.3 Hz,1.4 Hz),7.38(1H,dd,J=5.3 Hz,2.5Hz),7.45(1H,dd,J=2.5 Hz,1.4 Hz).

EXAMPLE 35(E)-N-ethyl-N-(6,6-dimethyl-2-octen-4-ynyl)-2-[2-[3-(3-thienyl)phenoxy]ethoxy]ethylaminehydrochloride

m.p.:96.5°-98° C.

IR(KBr,cm⁻¹): 2974,2926,2626,1599,1464,1449,1221,1128, 1089,1062,774.

¹ H-NMR(300 MHz,CDCl₃,δ ppm):0.94(3H,t,J=7.4 Hz),1.17(6H,s),1.40(3H,t,J=7.4 Hz),1.43(2H,q,J=7.4 Hz),3.11-3.19(2H,m),3.21(2H,t,J=4.6 Hz),3.77(2H,t,J=7.6 Hz),3.87-3.90(2H,m),4.10-4.15(2H,m),4.16-4.20(2H,m),5.87(1H,d,J=16.0Hz),6.18(1H,dt,J=16.0 Hz,7.6 Hz),6.83(1H,ddd,J=8.0 Hz, 2.8 Hz,1.0Hz),7.13(1H,dd,J=2.8 Hz,1.9 Hz),7.20(1H,ddd,J=8.0 Hz,1.9 Hz,1.0Hz),7.30(1H,t,J=8.0 Hz),7.35-7.40(2H,m), 7.45(1H,dd,J=2.7 Hz,1.7 Hz).

EXAMPLE 36(E,E,E)-N-ethyl-N-(6,6-dimethyl-2-hepten-4-ynyl)-3-[5-(3-thienyl)-2,4-pentadienyl]benzylamine

IR(neat,cm⁻¹): 2968,1263,1092,1038,987,801.

¹ H-NMR(300 MHz,CDCl₃,δ ppm):1.04(3H,t,J=7.1 Hz),1.23(9H,s),2.51(2H,q,J=7.1 Hz),3.09(2H,dd,J=6.4 Hz,1.5 Hz),3.46 (2H,dd,J=6.7Hz,1.5 Hz),3.54(2H,s),5.64(1H,dt,J=15.9 Hz, 1.5 Hz),5.92(1H,dt,J=15.2Hz,6.7 Hz),6.08(1H,dt,J=15.9 Hz, 6.4 Hz),6.20(1H,ddt,J=15.2 Hz,10.1Hz,1.5 Hz),6.49(1H,d,J=15.6 Hz),6.62(1H,dd,J=15.6 Hz,10.1Hz),7.07(1H,d,J=7.4 Hz),7.11(1H,dd,J=3.1 Hz,1.2 Hz),7.07-7.24(5H,m).

EXAMPLE 37(E,E)-N-ethyl-N-(2-fluoro-6,6-dimethyl-2-hepten-4-ynyl)-5-[3-(3-thienyl)-2-propenyloxymethyl]-2-furylmethylamine

IR(neat,cm⁻¹): 2968,2860,1677,1365,1266,1101,1059,798.

¹ H-NMR(300 MHz,CDCl₃,δ ppm):1.08(3H,t,J=7.1 Hz),1.26(9H,s),2.58(2H,q,J=7.1 Hz),3.21(2H,d,J=13.7 Hz),3.70(2H,s), 4.15(2H,dd,J=6.4Hz,1.5 Hz),4.46(2H,s),5.04(1H,d,J=33.8 Hz),6.13(1H,dt,J=16.0 Hz,6.4Hz),6.15(1H,d,J=3.0 Hz), 6.26(1H,d,J=3.0 Hz),6.62(1H,dt,J=16.0 Hz,1.5Hz),7.16(1H, dd,J=3.0 Hz,1.2 Hz),7.21(1H,dd,J=5.1 Hz,1.2 Hz),7.26(1H,dd,J=5.1 Hz,3.0 Hz).

EXAMPLE 38(E,E)-N-methyl-N-(6,6-dimethyl-2-hepten-4-ynyl)-5-[3-(3-thienyl)-2-propenyloxymethyl]-2-furylmethylamine

IR(neat,cm⁻¹): 2968,2860,1365,1110,1065,1020,966,798.

¹ H-NMR(300 MHz,CDCl₃,δ ppm):1.24(9H,s),2.23(3H,s),3.05 (2H,dd,J=6.9Hz,1.5 Hz),3.53(2H,s),4.13(2H,dd,J=6.3 Hz, 1.5Hz),4.46(2H,s),5.63(1H,dt,J=15.9 Hz,1.5 Hz),6.06(1H,dt, J=15.9 Hz,6.9Hz),6.13(1H,dt,J=15.9 Hz,6.3 Hz),6.14(1H,d,J= 3.0 Hz),6.26(1H,d,J=3.0Hz),6.62(1H,dt,J=15.9 Hz,1.5 Hz), 7.15(1H,dd,J=2.7 Hz,1.2Hz),7.20(1H,dd,J=3.6 Hz,1.2 Hz), 7.25(1H,dd,J=3.6 Hz,2.7 Hz).

EXAMPLE 39(E,E)-N-(6-methoxy-6-methyl-2-hepten-4-ynyl)-N-methyl-5-[3-(3-thienyl)-2-propenyloxymethyl]-2-furylmethylamine

IR(neat,cm⁻¹): 2986,2938,2848,2794,1660,1560,1458,1362,1248,1173,1074,966,768.

¹ H-NMR(300 MHz,CDCl₃,δ ppm):1.46(6H,s),2.25(3H,s),3.08 (2H,dd,J=6.6Hz,1.5 Hz),3.35(3H,s),3.54(2H,s),4.15(2H, dd,J=6.6 Hz,1.5Hz),4.47(2H,s),5.68(1H,dt,J=15.6 Hz,1.5Hz),6.09-6.21(3H,m),6.27(1H,d,J=3.3 Hz),6.62(1H,d,J=15.9Hz),7.15(1H,dd,J=3.0 Hz,1.5 Hz),7.21(1H,dd,J=5.4 Hz, 1.5Hz),7.25-7.27(1H,m).

EXAMPLE 40(E,E)-N-ethyl-N-(6,6-dimethyl-2-hepten-4-ynyl)-5-[3-(3-thienyl)-2-propenyloxymethyl]-2-furylmethylamine

IR(neat,cm⁻¹): 2968,2932,2866,1461,1365,1269,1200,1107,1068,1020,966,795,768.

¹ H-NMR(300 MHz,CDCl₃,δ ppm):1.06(3H,t,J=7.2 Hz),1.24(9H,s),2.51(2H,q,J=7.2 Hz),3.13(2H,dd,J=6.6 Hz,1.5 Hz),3.63(2H,s),4.14(2H,dd,J=6.3 Hz,1.5 Hz),4.46(2H,s),5.65(1H, dt,J=15.9 Hz,1.5Hz),6.05(1H,dt,J=15.9 Hz,6.6 Hz),6.13(1H, d,J=3.3 Hz),6.14(1H,dt,J=15.9Hz,6.3 Hz),6.26(1H,d,J=3.3 Hz),6.62(1H,d,J=15.9 Hz),7.16(1H,dd,J=3.0Hz,1.2 Hz), 7.21(1H,dd,J=5.1 Hz,1.2 Hz),7.26(1H,dd,J=5.1 Hz,3.0 Hz).

EXAMPLE 41(E,E)-N-(6-ethoxy-6-methyl-2-hepten-4-ynyl)-N-ethyl-5-[3-(3-thienyl)-2-propenyloxymethyl]-2-furylmethylamine

IR(neat,cm⁻¹): 2980,2932,1161,1110,1071,966.

¹ H-NMR(300 MHz,CDCl₃,δ ppm):1.07(3H,t,J=7.0 Hz),1.20(3H,t, J=7.1Hz),1.47(6H,s),2.52(2H,q,J=7.0 Hz),3.15(2H,dd,J=6.6 Hz,1.5Hz),3.59(2H,q,J=7.1 Hz),3.63(2H,s),4.14(2H,dd, J=6.0 Hz,1.5Hz),4.46(2H,s),5.68(1H,dt,J=15.8 Hz,1.5 Hz),6.08-6.20(3H,m),6.26(1H,d,J=3.2 Hz),6.62(1H,d,J=15.9Hz),7.14-7.19(3H,m).

EXAMPLE 42(E,E)-N-(6-methoxy-6-methyl-2-hepten-4-ynyl)-N-propyl-5-[3-(3-thienyl)-2-propenyloxymethyl]-2-furylmethylamine

IR(neat,cm⁻¹): 2926,2854,1467,1173,1077,966,759.

¹ H-NMR(300 MHz,CDCl₃,δ ppm):0.88(3H,t,J=7.3 Hz),1.46(6H,s),1.40-1.53(2H,m),2.37-2.42(2H,m),3.15(2H,dd,J=6.3 Hz, 1.5Hz),3.36(3H,s),3.63(2H,s),4.14(2H,dd,J=6.3 Hz,1.5Hz),4.46(2H,s),5.71(1H,dt,J,=16.0 Hz,1.5 Hz),6.13(1H,d, J=3.2Hz),6.15(1H,dt,J=16.0 Hz,6.3 Hz),6.26(1H,d,J=3.2 Hz),6.62(1H,d,J=l6.0Hz),7.l5(1H,dd,J=2.8 Hz,1.5 Hz), 7.21(1H,dd,J=5.2 Hz,1.5Hz),7.26(1H,dd,J=5.2 Hz,2.8 Hz).

EXAMPLE 43(E,E)-N-(2-fluoroethyl)-N-(6-methoxy-6-methyl-2-hepten-4-ynyl)-5-3-(3-thienyl)-2-propenyloxymethyl]-2-furylmethyl-amine

IR(neat,cm⁻¹): 1173,1107,1074,1020,966,768.

¹ H-NMR(300 MHz,CDCl₃,δ ppm):1.46(6H,s),2.81(2H,dt,J=26.4 Hz,5.0Hz),3.24(2H,dd,J=1.5 Hz,6.3 Hz),3.35(3H,s),3.72 (2H,s),4.15(2H,dd,J=6.5Hz,1.5 Hz),4.46(2H,s),4.51(2H, dt,J=44.7 Hz,5.0 Hz),5.71(1H,dt,J=15.8Hz,1.5 Hz),6.08-6.20(3H,m),6.27(1H,d,J=2.8 Hz),6.62(1H,d,J=15.9 Hz),7.16(1H,dd,J=3.0 Hz,1.2 Hz),7.21(1H,dd,J=5.1 Hz,1.2 Hz),7.26(1H,dd,J=5.1 Hz,3.0 Hz).

EXAMPLE 44(E,E)-N-cyclopropyl-N-(6-methoxy-6-methyl-2-hepten-4-ynyl)-5-3-(3-thienyl)-2-propenyloxymethyl]-2-furylmethylamine

IR(neat,cm⁻¹): 2986,2932,1362,1170,1074,966.

¹ H-NMR(300 MHz,CDCl₃,δ ppm):0.36-0.51(4H,m),1.46(6H,s),1.82-1.90(1H,m),3.27(2H,dd,J=6.9 Hz,1.5 Hz),3.35(3H,s),3.73(2H,s),4.14(2H,dd,J=6.1 Hz,1.5 Hz),4.46(2H,s),5.67 (1H,dt,J=15.9Hz,1.5 Hz),6.08-6.22(3H,m),6.26(1H,d,J=2.8 Hz),6.62(1H,d,J=15.9Hz),7.15(1H,dd,J=3.0 Hz,1.5 Hz), 7.21(1H,dd,J=5.1 Hz,1.5Hz),7.26(1H,dd,J=5.1 Hz,3.0 Hz).

EXAMPLE 45 Production of(E)-N-ethyl-N-(6,6-dimethyl-4-hepten-2-ynyl)-2-[2-[3-(3-thienyl)phenoxy]ethoxy]ethylamine

35 mg of (E)-6,6-dimethyl-4-hepten-2-yn-1-ol was dissolved in 2 ml ofethyl acetate, and 23 μl of methanesulfonyl chloride and 70 μl oftriethylamine were added under ice cooling. The mixture was stirred for30 min. The precipitate was removed by filtration, and the s solvent wasevaporated under reduced pressure. The residue was dissolved in 2 ml ofdimethylformamide, and a dimethylformamide solution(2 ml) of 58 mg ofN-ethyl- 2-[2-[3-(3-thienyl)phenoxy]ethoxy]ethylamine and 55 mg ofpotassium carbonate were added. The mixture was stirred overnight atroom temperature and then ethyl ether and water were added. The organiclayer was separated, washed with a saturated aqueous solution of sodiumchloride, and dried over anhydrous magnesium sulfate. The desiccant wasseparated by filtration, and the solvent was evaporated. The residue waspurified by silica gel column chromatography [hexane/ethylacetate=4/1→2/1] to give 40 mg (yield 49%) of the captioned compound asa pale brown oil.

IR(neat,cm⁻¹): 2962,1287,1128,771.

¹ H-NMR(300 MHz,CDCl₃,δ ppm):1.02(9H,s),1.08(3H,t,J=7.0Hz),2.62(2H,q,J=7.2 Hz),2.78(2H,t,J=5.8 Hz),3.58(2H,d,J=1.6Hz),3.70(2H,t,J=5.8 Hz),3.85(2H,t,J=5.0 Hz),4.18(2H, t,J=5.0Hz),5.40(1H,dt,J=16.0 Hz,1.6 Hz),6.14(1H,d,J=16.0 Hz),6.85(1H,ddd,J=8.4Hz,2.4 Hz,1.4 Hz),7.15-7.20(2H, m),7.30(3H,t,J=7.8 Hz),7.44(1H,t,J=2.2Hz).

Compound of Example 46 to 49 was obtained by performing the samereaction as in Example 45 except that the corresponding4-hepten-2-yn-1-ol or 2,4-heptadiyn-1-ol derivative, and2-furylmethlamine derivative were used instead of the starting compound,(E)-6,6-dimethyl-4-hepten-2-yn-1-ol andN-ethyl-2-[2-[3-(3-thienyl)phenoxy]ethoxy]ethylamine, which were used inthe above-mentioned reaction.

EXAMPLE 46(E,E)-N-ethyl-N-(6,6-dimethyl-4-hepten-2-ynyl)-5-3-(3-thienyl)-2-propenyloxymethyl]-2-furylmethylamine

IR(neat,cm⁻¹): 2962,2866,1365,1101,1068,1020,966,792,768.

¹ H-NMR(300 MHz,CDCl₃,δ ppm):1.03(9H,s),1.11(3H,t,J=7.2Hz),2.58(2H,q,J=7.2 Hz),3.49(2H,d,J=2.0 Hz),3.67(2H,s), 4.15(2H,dd,J=6.0Hz,1.5 Hz),4.46(2H,s),5.43(1H,dt,J=16.5 Hz,2.0 Hz),6.14(1H,dt,J=15.9Hz,6.0 Hz),6.16(1H,d,J=16.5 Hz),6.21(1H,d,J=3.2 Hz),6.26(1H,d,J=3.2Hz),6.62(1H, d,J=15.9 Hz),7.15-7.27(3H,m).

EXAMPLE 47(E,E)-N-(6-methoxy-6-methyl-2,4-heptadiynyl)-N-methyl-5-[3-(3-thienyl)-2-propenyloxymethyl]-2-furylmethylamine

IR(neat,cm⁻¹): 2986,2938,1362,1269,1173,1110,1074,1020, 966,768.

¹ H-NMR(300 MHz,CDCl₃,δ ppm):1.48(6H,s),2.36(3H,s),3.37(3H,s),3.44(2H,s),3.60(2H,s),4.15(2H,dd,J=6.2 Hz,1.2Hz),4.46(2H,s),6.13(1H,dt,J=15.6 Hz,6.2 Hz),6.22(1H,d,J=3.2Hz),6.27(1H,d,J=3.2 Hz),6.62(1H,dt,J=15.6 Hz,1.2 Hz), 7.15(1H,dd,J=3.0Hz,0.9 Hz),7.21(1H,dd,J=4.5 Hz,0.9 Hz), 7.26(1H,dd,J=4.5 Hz,3.0 Hz).

EXAMPLE 48(E)-N-ethyl-N-(6-methoxy-6-methyl-2,4-heptadiynyl)-5-[3-(3-thienylmethoxy)-1-propenyl]-2-furylmethylamine

IR(neat,cm⁻¹): 2986,2938,1266,1173,1134,1110,1074,966, 777.

¹ H-NMR(300 MHz,CDCl₃,δ ppm):1.12(3H,t,J=7.2 Hz),1.47(6H,s),2.61(2H,q,J=7.2 Hz),3.37(3H,s),3.48(2H,s),3.67(2H,s),4.14(2H,dd,J=5.4 Hz,1.2 Hz),4.56(2H,s),6.18(1H,d,J=3.0Hz),6.23(1H,d,J=3.0 Hz),6.23(1H,dt,J=15.9 Hz,5.4 Hz), 6.40(1H,dt,J=15.9Hz,1.2 Hz),7.09(1H,dd,J=4.8 Hz,1.2 Hz), 7.22(1H,dd,J=2.7 Hz,1.2Hz),7.30(1H,dd,J=4.8 Hz,2.7 Hz).

EXAMPLE 49(E,E)-N-ethyl-N-(6-methoxy-6-methyl-4-hepten-2-ynyl)-5-[3-(3-thienyl)-2-propenyloxymethyl]-2-furylmethylamine

IR(neat,cm ): 2980,2938,2416,1464,1197,1170,1110,1071, 1020,966.

¹ H-NMR(300 MHz,CDCl₃,δ ppm):1.28(6H,s),1.49(3H,t,J=7.0Hz),3.18(3H,s),3.12-3.20(2H,m),3.90-4.06(2H,m),4.16 (2H,dd,J=6.0 Hz,1.5Hz),4.22-4.38(2H,m),4.48(2H,s),5.65 (1H,dt,J=16.4 Hz,1.5Hz),6.12(1H,dt,J=1.60 Hz,6.0 Hz),6.24 (1H,d,J=16.4 Hz),6.40(1H,d,J=3.5Hz),6.86(1H,d,J=3.5 Hz), 6.62(1H,d,J=16.0Hz),7.16-7.22(2H,m),7.26-7.29(1H,m).

EXAMPLE 50 Production of(E)-N-ethyl-N-(6,6-dimethyl-4-heptynyl)-3-[3-(3-thienyl)-2-propenyloxymethyl]benzylamine

30 mg of (E)-N-ethyl-3-[3-(3-thienyl)-2-propenyloxymethyl]benzylaminewas dissolved in 0.3 ml of dimethylformamide, and 22mg of6,6-dimethyl-4-heptynyl methanesulfonate, 9.0 mg of potassium iodide and6.0 μl of pyridine were added. The mixture was stirred at 50° C. for 4hours, and then ethyl ether and water were added. The organic layer wasseparated, washed with a saturated aqueous solution of sodium chloride,and dried over anhydrous magnesium sulfate. The desiccant was separatedby filtration, and the solvent was evaporated. The residue was purifiedby silica gel column chromatography [hexane/ethyl acetate=5/1] to give11 mg (yield 26%) of the captioned compound as a colorless oil.

IR(neat,cm⁻¹): 2968,2866,1458,1365,1155,1110,1071,966, 765.

¹ H-NMR(300 MHz,CDCl₃,δ ppm):1.03(3H,t,J=7.1 Hz),1.16(9H,s),1.63(2H,quint.,J=7.1 Hz),2.16(2H,t,J=7.1 Hz),2.49(2H, q,J=7.1Hz),2.52(2H,t,J=7.1 Hz),3.56(2H,s),4.15(2H,dd,J=6.1 Hz,1.5Hz),4.55(2H,s),6.17(1H,dt,J=15.9 Hz,6.1 Hz), 6.64(1H,dt,J=15.9 Hz,1.5Hz),7.16(1H,dd,J=2.6 Hz,1.2 Hz), 7.18-7.31(2H,m).

Compound of Example 51 was obtained by performing the same reaction asin Example 51 was obtained by performing the same reaction as in Example50 except that N-ethyl-2-[2-[3-(3-thienyl)phenoxy]ethoxy]ethylamine wasused instead of the starting compound,(E)-N-ethyl-3-[3-(3-thienyl)-2-propenyloxymethyl] benzylamine, which wasused in the above-mentioned reaction.

EXAMPLE 51N-ethyl-N-(6,6-dimethyl-4-heptynyl)-2-[2-[3-(3-thienyl)phenoxy]ethoxy]ethylamine

IR(neat,cm⁻¹): 2968,1605,1584,1455,1290,1269,1221,1188, 1128,1059,774.

¹ H-NMR(300 MHz,CDCl₃,δ ppm):1.07(3H,t,J=7.1 Hz),1.18(9H,s),1.64(2H,quint.,J=7.4 Hz),2.16(2H,t,J=7.4 Hz),2.62(2H, t,J=7.4Hz),2.63(2H,q,J=7.1 Hz),2.74(2H,t,J=6.4 Hz),3.68 (2H,t,J=6.4Hz),3.85(2H,t,J=5.0 Hz),4.17(2H,t,J=5.0 Hz), 6.85(1H,ddd,J=8.0 Hz,2.3Hz,0.9 Hz),7.15-7.21(2H,m),7.30 (1H,t,J=8.0 Hz),7.37(2H,d,J=1.8Hz),7.44(2H,t,J=1.8 Hz).

EXAMPLE 52 Production of(E)-N-(6-methoxy-6-methyl-2-hepten-4-ynyl)-5-[3-(3-thienyl)phenoxy]pentylamine

100 mg of 5-[3-(3-thienyl)phenoxy]pentylamine and 100 mg of potassiumcarbonate were dissolved in 5 ml of dimethylformamide, and adimethylformamide solution (0.5 ml) of 43 mg of(E)-6-methoxy-6-methyl-2-hepten-4-ynyl bromide (contaminated with about5 wt % of the (Z)-isomer) was added dropwise over 30 minutes withstirring. The mixture was stirred at room temperature for 1 hour. Thesolvent was evaporated under reduced pressure, and ethyl acetate andwater were added to the residue to extract it. The organic layer wasseparated, washed with a saturated aqueous solution of sodium chloride,and dried over anhydrous magnesium sulfate. The desiccant was separatedby filtration, and the solvent was evaporated. The residue was purifiedby silica gel column chromatography [methylene chloride→methylenechloride/methanol=10/1] to give 31 mg (yield 39%) of the captionedcompound as a pale yellow oil.

IR(neat,cm⁻¹): 2938,1605,1584,1218,1173,1074,771.

¹ H-NMR(300 MHz,CDCl₃,δ ppm):1.45(6H,s),1.49-1.57(4H,m), 1.83(2H,q,J=7.0Hz),2.64(2H,t,J=7.0 Hz),3.30(2H,dd,J=6.1 Hz,1.5Hz),3.35(3H,s),4.00(2H,t,J=7.0 Hz),5.67(1H,dt, J=16.2 Hz,1.5Hz),6.19(1H,dt,J=16.2 Hz,6.1 Hz),6.82(1H, ddd,J=7.5 Hz,2.7 Hz,0.9Hz),7.12(1H,dd,J=2.7 Hz,0.9 Hz), 7.17(1H,dt,J=7.5 Hz,0.9Hz),7.30(1H,t,J=7.5 Hz),7.37(2H, d,J=2.2 Hz),7.44(1H,d,J=2.2 Hz).

Compound of Example 53 was obtained by performing the same reaction asin Example 52 except that 2-[2-[3-(3-thienyl)phenoxy]ethoxy]ethylamineand (E)-6,6-dimethyl-2-hepten-4-ynyl bromide were used instead of thestarting compounds, 5-[3-(3-thienyl)phenoxy]pentylamine and(E)-6-methoxy-6-methyl-2-hepten-4-ynyl bromide, which were used in theabove-mentioned reaction.

EXAMPLE 53(E)-N-(6,6-dimethyl-2-hepten-4-ynyl)-2-[2-[3-(3-thienyl)phenoxy]ethoxy]ethylaminehydrochloride

m.p.:105°-107° C.

IR(KBr,cm⁻¹): 2968,2770,1611,1584,1452,1290,1269,1218,1188,1134,1068,765.

¹ H-NMR(300 MHz,CDCl₃,δ ppm):1.20(9H,s),3.14(2H,t,J=5.0Hz),3.71(2H,d,J=7.1 Hz),3.80-3.90(2H,m),3.96(2H,t,J=5.0Hz),4.19-4.23(2H,m),5.84(1H,d,J=15.6 Hz),6.16(1H,dt, J=15.6 Hz,7.1Hz),6.84(1H,ddd,J=7.5 Hz,2.4 Hz,1.0 Hz),7.15-7.21(2H,m),7.29(1H,t,J=7.5Hz),7.34-7.40(2H,m),7.45-7.48(1H,m).

EXAMPLE 54 Production of(E)-N-(6,6-dimethyl-2-hepten-4-ynyl)-N-propargyl-2-[2-[3-(3-thienyl)phenoxy]ethoxy]ethylaminehydro-chloride

680 mg of(E)-N-(6,6-dimethyl-2-hepten-4-ynyl)-2-[2-[3-(3-thienyl)phenoxy]ethoxy]ethylaminewas dissolved in 50 ml of dimethylformamide, and 300 mg of propargylbromide and 500 mg of potassium carbonate were added. The mixture wasstirred under ice cooling for 3 hours. The solvent was evaporated underreduced pressure, and the residue was dissolved in ethyl ether. Aninsoluble material was removed by filtration, and the filtrate wasevaporated under reduced pressure. The residue was then purified bysilica gel short column chromatography, followed by medium-pressureliquid chromatography [silica gel column, methylenechloride/methanol=20/1] to give 350 mg (yield 61%) of free base of thecaptioned compound as a colorless oil. The resulting free base wastreated with a hydrogen chloride-methanol solution and crystallized fromethyl ether to give the captioned compound as a colorless crystallinepowder, m.p. 111°-113° C.

IR(KBr,cm⁻¹): 2968,2932,2380,2314,1605,1584,1452,1290,1221,1188,1137,1068,774.

¹ H-NMR(300 MHz,CDCl₃,δ ppm):1.23(9H,s),2.57(1H,s),3.31(2H,m),3.61-4.32(10H,m),5.89(2H,d,J=15.9 Hz),6.29(2H, dt,J=15.9 Hz,6.3Hz),6.84(1H,ddd,J=8.0 Hz,2.3 Hz,1.0 Hz), 7.15(1H,dd,J=2.3 Hz,1.4Hz),7.20(1H,ddd,J=7.5 Hz,1.4 Hz, 1.0 Hz),7.31(1H,dd,J=8.0 Hz,7.5Hz),7.38(2H,d,J=2.2 Hz), 7.46(1H,t,J=2.2 Hz).

Compound of Example 55 was obtained by performing the same reaction asin Example 54 except that allyl bromide was used instead of the startingcompound, propargyl bromide, which was used in the above-mentionedreaction.

EXAMPLE 55(E)-N-allyl-N-(6,6-dimethyl-2-hepten-4-ynyl)-2-[2-[3-(3-thienyl)phenoxy]ethoxy]ethylamine

IR(neat,cm⁻¹): 2968,1605,1452,1365,1287,1221,1185,1128, 1047,963,771.

¹ H-NMR(300 MHz,CDCl₃,δ ppm):1.23(9H,s),2.69(2H,t,J=5.9Hz),3.14(2H,d,J=6.4 Hz),3.18(2H,dd,J=6.6 Hz,1.5 Hz),3.64 (2H,t,J=5.9Hz),3.82(2H,t,J=4.9 Hz),4.16(2H,t,J=4.9 Hz),5.09-5.20(2H,m),5.62(1H,dt,J=15.9 Hz),1.5 Hz),5.83(1H, ddt,J=17.0 Hz,9.8Hz,6.4 Hz),6.04(1H,dt,J=1.59 Hz),6.6 Hz), 6.85(1H,ddd,J=7.9 Hz,2.3Hz,1.0 Hz),7.15-7.20(2H,m),7.30 (1H,t,J=7.9 Hz),7.37(2H,d,J=2.5Hz),7.44(1H,t,J=2.5 Hz).

EXAMPLE 56 Production of(E)-N-ethyl-N-(7,7,7-trifluoro-6-trifluoromethyl-6-methoxy-2-hepten-4-ynyl)-2-[2-[3-(3-thienyl)-phenoxy]ethoxy]ethylamine

159 mg of(E)-ethyl-N-(7,7,7-trifluoro-6-trifluoromethyl-6-hydroxy-2-hepten-4-ynyl)-2-[2-[3-(3-thienyl)phenoxy]ethoxy]ethylaminewas dissolved in 2 ml of dimethylformamide, and 24 mg of 60% oily sodiumhydride was added. The mixture was stirred at room temperature for 10minutes. To this solution was added 60 μl of dimethyl sulfate, and thenthe mixture was stirred at room temperature for 4 hours. The solvent wasevaporated under reduced pressure, and ethyl acetate and water wereadded to the residue to extract it. The organic layer was separated,washed with a saturated aqueous solution of sodium chloride, and driedover anhydrous magnesium sulfate. The desiccant was separated byfiltration, and the solvent was evaporated. The residue was purified bysilica gel column chromatography [methylene chloride/methanol=70/1] togive 24 mg (yield 15%) of the captioned compound as a pale yellow oil.

IR(neat,cm⁻¹): 2230,1584,1491,1257,1158,1059,963.

¹ H-NMR(300 MHz,CDCl₃,δ ppm):1.04(3H,t,J=7.1 Hz),2.58(2H,q, J=7.1Hz),2.73(2H,t,J=5.7 Hz),3.27(2H,d,J=5.4 Hz),3.65 (2H,t,J=5.7Hz),3.66(3H,s),3.83(2H,t,J=4.8 Hz),4.17(2H, t,J=4.8 Hz),5.79(1H,d,J=15.9Hz),6.45(1H,dt,J=15.9 Hz, 5.4 Hz),6.85(1H,ddd,J=8.1 Hz,2.4 Hz,1.7Hz),7.17(1H,ddd,J=8.1 Hz,2.4 Hz,1.7 Hz),7.19-7.21(1H,m),7.30(1H,t,J=8.1Hz), 7.37(1H,d,J=1.8 Hz),7.38(1H,d,J=2.7 Hz),7.43(1H,dd,J=2.7 Hz,1.8Hz).

EXAMPLE 57 Production of(E)-N-ethyl-N-(6,7,7,7-tetrafluoro-6-trifluoromethyl-2-hepten-4-ynyl)-2-[2-3-(3-thienyl)phenoxy]ethoxy]ethylamine

150 mg of(E)-N-ethyl-N-(7,7,7-trifluoro-6-trifluoromethyl-6-hydroxy-2-hepten-4-ynyl)-2-[2-[3-(3thienyl)phenoxy]ethoxy]ethylaminewas dissolved in 3 ml of methylene chloride, and under a nitrogenatmosphere, 29 μl of dimethylaminosulfur trifluoride was added at -78°C. The mixture was gradually warmed to room temperature with stirring,and the solution was washed s with water, then dried over anhydrousmagnesium sulfate. The desiccant was separated by filtration, and thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography [methylene chloride→methylenechloride/methanol=10/1] to give 113 mg (yield 70%) of the captionedcompound as a pale yellow oil.

IR(neat,cm⁻¹): 2926,1605,1584,1287,1257,1218,1200,960, 774.

¹ H-NMR(300 MHz,CDCl₃,δ ppm):1.02(3H,t,J=7.1 Hz),2.59(2H,q, J=7.1Hz),2.71(2H,t,J=6.0 Hz),3.23(2H,dd,J=6.9 Hz,1.5 Hz), 3.69(2H,t,J=6.0Hz),3.78(2H,t,J=6.2 Hz),4.14(2H,d,J=6.2 Hz),5.65(1H,dt,J=16.2 Hz,1.5Hz),6.52(1H,dt,J=16.2 Hz, 6.9 Hz),6.83(1H,ddd,J=7.5 Hz,2.7 Hz,1.5Hz),7.13(1H,dd,J=2.7 Hz,1.8 Hz),7.19(1H,ddd,J=7.5 Hz,1.8 Hz,1.5Hz),7.30(1H, t,J=7.5 Hz),7.35(1H,dd,J=5.1 Hz,1.5 Hz),7.37(1H,dd,J=5.1Hz,2.7 Hz),7.43(1H,dd,J=2.7 Hz,1.5 Hz).

EXAMPLE 58 Production ofN-ethyl-N-(6-methoxy-6-methyl-2,4-heptadiynyl)-2-2-3-(3-thienyl)phenoxy]ethoxy]ethylamine

180 mg ofN-ethyl-N-propargyl-2-[2-[3-(3-thienyl)phenoxy]ethoxy]ethylamine[synthesized by reacting N-ethyl-2-[2-[3-(3-thienyl)phenoxy]ethoxy]ethylamine with propargyl bromide], 5.4 mg of copper(I) chloride and 57mg of hydroxylamine hydrochloride were dissolved in a mixture of 0.8 mlof a 70% aqueous ethylamine solution and 1 ml of methanol. Under icecooling, 1.5 g of 1-bromo-4-methoxy-4-methyl-1-butyne was added dropwiseover 10 minutes, and the mixture was stirred overnight at roomtemperature. The solvent was evaporated under reduced pressure, andethyl acetate and water were added to the residue to extract it. Theorganic layer was separated, washed with a saturated aqueous solution ofsodium chloride, and dried over anhydrous magnesium sulfate. Thedesiccant was separated by filtration, and the solvent was evaporatedunder reduced pressure. The residue was purified by silica gel columnchromatography [hexane/ethyl acetate=10/1→5/1→3/1] to give 86.0 mg(yield 37%) of the captioned compound as a colorless oil.

IR(neat,cm⁻¹): 2980,2938,1605,1452,1269,1131,1074,771.

¹ H-NMR(300 MHz,CDCl₃,δ ppm):1.07(3H,t,J=7.0 Hz),1.46(6H,s),2.61(2H,q,J=7.0 Hz),2.77(2H,t,J=5.8 Hz),3.35(3H,s),3.58(2H,s),3.68(2H,t,J=5.8 Hz),3.85(2H,t,J=5.0 Hz),4.18 (2H,t,J=5.0Hz),6.85(1H,ddd,J=8.0 Hz,2.3 Hz,0.9 Hz),7.14-7.22(2H,m),7.30(1H,t,J=8.0Hz),7.37(2H,d,J=2.2 Hz),7.44 (1H,t,J=2.2 Hz).

Compound of Example 59 was obtained by performing the same reaction asin Example 58 except that(E)-N-ethyl-N-propargyl-5-[3-(3-thienyl)-2-propen-yloxymethyl]-2-furylmethylamine was used instead of the starting compound,N-ethyl-N-propargyl-2-[2-[3-(3-thienyl)phenoxy]ethoxy]ethylamine, whichwas used in the above-mentioned reaction.

EXAMPLE 59(E)-N-(6-methoxy-6-methyl-2,4-heptadiynyl)-5-[3-(3-thienyl)-2-propenyloxymethyl]-2-furylmethylamine

IR(neat,cm⁻¹): 2986,1461,1362,1266,1173,1074,969.

¹ H-NMR(300 MHz,CDCl₃,δ ppm):1.11(3H,t,J=7.0 Hz),1.47(6H,s),2.61(2H,q,J=7.0 Hz),3.37(3H,s),3.47(2H,s),3.67(2H,s),4.15(2H,dd,J=6.3 Hz,1.6 Hz),4.46(2H,s),6.14(H,dt,J=15.9 Hz,6.3Hz),6.22(1H,d,J=3.0 Hz),6.27(1H,d,J=3.0 Hz), 6.62(1H,d,J=15.9Hz),7.14-7.17(1H,m),7.19-7.22(1H,m), 7.24-7.28(1H,m).

EXAMPLE 60 Production of(E)-N-ethyl-N-(6,6-dimethyl-2-hepten-4-ynyl)-5-[3-(3-thienyl)phenoxy]-3-oxopentylamine

0.82 g of 1,5-dihydroxy-3,3-dimethoxypentane was dissolved in 30 ml ofethyl acetate, and 0.47 ml of methanesulfonyl chloride and 0.8 ml oftriethylamine were added. The mixture was stirred under ice cooling for1 hour, and then the solution was washed successively with a saturatedaqueous solution of sodium bicarbonate and water, followed by dried overanhydrous magnesium sulfate. The desiccant was separated by filtration,and the solvent was then evaporated under reduced pressure. The residuewas dissolved in 10 ml of dimethylformamide, and 1.5 g of(E)-N-ethyl-6,6-dimethyl-2-hepten-4-ynylamine hydrochloride, 1.1 g ofpotassium carbonate and 0.1 g of potassium iodide were added. Themixture was heated at 70° C. for 5 hours, and the solvent was evaporatedunder reduce pressure. The residue was worked up in a customary manner,and then purified by silica gel column chromatography [hexane/ethylacetate=10/1 ] to give 0.23 g (yield 14%) of(E)-N-ethyl-N-(6,6-dimethyl-2-hepten-4-ynyl)-5-hydroxy-3,3-dimethoxypentylamine.

0.22 g of the resulting amino alcohol compound was dissolved in 5 ml ofethyl acetate, and 60 μl of methanesulfonyl chloride and 0.1 ml oftriethylamine were added. The mixture was stirred at room temperaturefor 30 minutes, and then the solution was washed successively with asaturated aqueous solution of sodium bicarbonate and water, followed bydrying over anhydrous magnesium sulfate. The desiccant was separated byfiltration, and the solvent was evaporated under reduced pressure. Theresidue was added to 1 ml of a dimethylformamide solution of phenolateprepared from 0.13 g of 3-(3-thienyl)phenol and 30 mg of 60% oily sodiumhydride. The mixture was heated at 70° C. for 3 hours, and then thesolvent was evaporated under reduced pressure. The residue was worked upin a customary manner, and purified by silica gel column chromatography[hexane/ethyl acetate=5/1 ] to give 42 mg (yield 13%) of(E)-N-ethyl-N-(6,6-dimethyl-2-hepten-4-ynyl)-3,3-dimethoxy-5-[3-(3-thienyl)phenoxy]pentylamine.30 mg of the resulting ether compound was dissolved in 5 ml of ethylacetate, and 5 ml of 1 N hydrochloric acid was added. The mixture wasstirred at room temperature for 4 hours. The organic layer wasseparated, washed with water, and worked up in a customary manner. Theproduct was purified by silica gel column chromatography [hexane/ethylacetate=10/1] to give 25 mg (yield 88%) of the captioned compound as acolorless oil.

IR(neat,cm⁻¹): 2967,2801,1720,1601,1583,1491,1189.

¹ H-NMR(300 MHz,CDCl₃,δ ppm):1.01(3H,t,J=7.2 Hz),1.23(9H,s),2.41(2H,t,J=6.4 Hz),2.44(2H,t,J=6.1 Hz),2.57(2H,q,J=7.2Hz),3.18(2H,dd,J=6.5 Hz,1.4 Hz),3.81(2H,t,J=6.4 Hz), 4.07(2H,t,J=6.1Hz),5.67(1H,dt,J=15.9 Hz,1.4 Hz),6.07(1H, dt,J=15.9 Hz,6.5Hz),6.85(1H,ddd,J=7.8 Hz,2.8 Hz,1.4 Hz), 7.15-7.21(2H,m),7.29(1H,t,J=7.8Hz),7.37(2H,d,J=2.2 Hz), 7.45(1H,t,J=2.2 Hz).

EXAMPLE 61 Production of(E,E)-N-methyl-N-(6,6-dimethyl-2-hepten-4-ynyl)-2-3-[3-(3-thienyl)phenyl]-2-propenylthio]ethylamine

300 mg of (E)-2-[3-[3-(3-thienyl)phenyl]-2-propenyl-thio]ethylamine[synthesized by condensing 3-ethanethiol in the presence of base ]and170 mg of (E)-6,6-dimethyl-2-hepten-4-ynal were dissolved in a mixtureof 10 ml of ethanol and 5 ml of tetrahydrofuran. The mixture was thenallowed to stand for 1 hour, and the solvent was evaporated underreduced pressure. The residue was dissolved in 10 ml of ethanol, and thesolvent was evaporated again under reduced pressure. The residue wasdissolved in 10 ml of ethanol, and 50 mg of sodium borohydride wasadded, then the mixture was stirred at room temperature for 1 hour. Thesolvent was evaporated, and ethyl ether and water were added to theresidue to extract it. The organic layer was separated, washed with asaturated aqueous solution of sodium chloride, and dried over anhydrousmagnesium sulfate. The desiccant was separated by filtration, and thesolvent was evaporated under reduced pressure. The residue was purifiedby medium-pressure liquid chromatography [silica gel column, methylenechloride→methylene chloride/methanol=10/1] to give 147 mg (yield 34%) of(E,E)-N-(6,6-dimethyl-2-hepten-4-ynyl)-2-[3-(3-thienyl)phenyl]-2-propenylthio]ethylamine.

50 mg of the resulting amine compound was dissolved in 2 ml of ethanol,and 50 μl of 35% aqueous HCHO and 20 mg of NaBH₃ CN were added. Themixture was stirred at room temperature for 2 hours, and then thesolvent was evaporated under reduced pressure. The residue was worked upin a customary manner, and purified by medium-pressure liquidchromatography [silica gel column, methylene chloride→methylenechloride/ethyl acetate=5/1 ] to give 41 mg (yield 79%) of the captionedcompound as a colorless oil.

IR(neat,cm⁻¹):2968,2866,1605,1458,1365,1263,1206,1125,963,849,774,690,651.

¹ H-NMR(300 MHz,CDCl₃,δ ppm):1.23(9H,s),2.67(2H,t,J=6.5Hz),2.81(2H,t,J=6.5 Hz),3.28(2H,dd,J=6.4 Hz,1.5 Hz),3.32 (2H,d,J=7.3Hz),5.63(1H,dt,J=15.9 Hz,11.5 Hz),6.06(1H,dt, J=15.9 Hz,6.4Hz),6.23(1H,dt,J=15.6 Hz,7.3 Hz),6.48(1H,d, J=15.6Hz),7.29-7.37(2H,m),7.38-7.40(2H,m),7.45-7.49 (2H,m),7.58(1H,t,J=2.0Hz).

EXAMPLE 62 Production of(E,E)-N-ethyl-N-(6,6-dimethyl-2-hepten-4-ynyl)-3-[4-(3-thienyl)-3-butenyloxy]benzylamine

14 mg of (E)-4-(3-thienyl)-3-butenyl-1-ol was dissolved in 2 ml ofmethylene chloride, and 14 μl of methanesulfonyl chloride and 22 μl oftriethylamine were added. The mixture was stirred at room temperaturefor 3 hours. The precipitate was removed by filtration, and the solventwas evaporated under reduced pressure to give crude(E)-4-(3-thienyl)-3-butenyl methanesulfonate. 21 mg of(E)-N-ethyl-N-(6,6-dimethyl-2-hepten-4-ynyl)-3-hydroxybenzylamine wasdissolved in 2 ml of dimethylformamide, and 3 mg of 60% oily sodiumhydride was added. The mixture was stirred for 30 minutes, and adimethylformamide solution (1 ml) of the mesylated compound obtainedabove was added, then the mixture was stirred overnight at roomtemperature. The solvent was evaporated under reduce pressure, and ethylacetate and water were added to the residue to extract it. The organiclayer was separated, washed with a saturated aqueous solution of sodiumchloride, and dried over s anhydrous magnesium sulfate. The desiccantwas separated by filtration, and the solvent was evaporated underreduced pressure. The residue was purified by medium-pressure liquidchromatography [silica gel column, hexane/ethyl acetate=4/1 ] to give2.7 mg (yield 12%) of the captioned compound as a pale yellow oil.

IR(neat,cm⁻¹): 2972,2928,1602,1458,1266,1044,964.

¹ H-NMR(300 MHz,CDCl₃,δ ppm):1.05(3H,t,J=7.1 Hz),1.24(9H,s),2.51(2H,q,J=7.1 Hz),2.68(2H,dq,J=6.6 Hz,1.3 Hz),3.10 (2H,dd,J=6.5Hz,1.5 Hz),3.58(2H,s),4.06(2H,t,J=6.6 Hz), 5.65(1H,dt,J=15.8 Hz,1.5Hz),6.02-6.21(2H,m),6.54(1H,d, J=15.9 Hz),6.78(1H,dd,J=7.2 Hz,2.4Hz),6.88-6.95(2H,m), 7.12(1H,t,J=1.6 Hz),7.18-7.30(3H,m).

Compounds of Examples 63 and 64 were obtained by performing the samereaction as in Example 62 except that 2-(3-thienymethoxy)ethanol or(E)-N-methyl-N-(6,6-dimethyl-2-hepten-4-ynyl)-3-hydroxybenzylamine wasused instead of the starting compound, (E)-4-(3-thienyl)-3-buten-1-ol or(E)-N-ethyl-N-(6,6-dimethyl-2-hepten-4-ynyl)-3-hydroxybenzylamine, whichwas used in the above-mentioned reaction.

EXAMPLE 63(E,E]-N-methyl-N-(6,6-dimethyl-2-hepten-4-ynyl)-3-[4-(3-thienyl)-3-butenyloxy]benzylamine

IR(neat,cm⁻¹): 2968,2866,2788,1602,1584,1491,1455,1365, 1266,1041,765.

¹ H-NMR(300 MHz,CDCl₃,δ ppm):1.24(9H,s),2.18(3H,s),2.66 (2H,dq,J=6.7Hz,1.4 Hz),3.03(2H,dd,J=6.7 Hz,1.4 Hz),3.45 (2H,s),4.07(2H,t,J=6.7Hz),5.64(1H,dt,J=15.8 Hz,1.4 Hz), 6.09(1H,dt,J=15.8 Hz,6.7Hz),6.14(1H,dt,J=15.8 Hz,6.7 Hz), 6.53(1H,dt,J=15.8 Hz,1.4Hz),6.79(1H,dd,J=7.5 Hz,1.8 Hz), 6.87-6.91(2H,m),7.09(1H,d,J=2.7Hz),7.18-7.22(2H,m), 7.23-7.27(1H,m).

EXAMPLE 64(E)-N-ethyl-N-(6,6-dimethyl-2-hepten-4-ynyl)-3-2-(3-thienylmethoxy)ethoxy]benzylamine

IR(neat,cm⁻¹): 2968,2926,2866,2800,1455,1266,1107.

¹ H-NMR(300 MHz,CDCl₃,δ ppm):1.03(3H,t,J=7.1 Hz),1.24(9H,s),2.49(2H,q,J=7.1 Hz),3.08(2H,d,J=6.5 Hz),3.52(2H,s), 3.82(2H,t,J=4.9Hz),4.14(2H,t,J=4.9 Hz),4.64(2H,s),5.64 (1H,d,J=15.9Hz),6.07(1H,dt,J=15.9 Hz,6.5 Hz),6.79(1H,dd, J=7.8 Hz,2.3Hz),6.90(1H,d,J=7.8 Hz),6.94(1H,br.s),7.10 (1H,dd,J=4.9 Hz,1.2Hz),7.19(1H,t,J=7.8 Hz),7.23-7.26(1H, m),7.30(1H,dd,J=4.9 Hz,2.9 Hz).

EXAMPLE 65

Production of(E,E)-N-ethyl-N-(6,6-dimethyl-2-hepten-4-ynyl)-3-[3-(3-thienyl)-2-propenylthiomethyl]benzylamine

16 mg of S-[(E)-3-(3-thienyl)-2-propenyl]thioacetate was dissolved in 1ml of methanol, and 15 mg of(E)-N-ethyl-N-(6,6-dimethyl-2-hepten-4-ynyl)-3-chloromethylbenzylamineand 42 mg of potassium carbonate were added. The mixture was stirred atroom temperature for 3 hours. The solvent was evaporated under reducedpressure, and ethyl acetate and water were added to the residue toextract it. The organic layer was separated, washed with a saturatedaqueous solution of sodium chloride, and dried over anhydrous magnesiumsulfate. The desiccant was separated by filtration and the solvent wasevaporated under reduced pressure. The residue was purified bymedium-pressure liquid chromatography [silica gel column, hexane/ethylacetate=5/1] to give 21 mg (yield 97%) of the captioned compound as acolorless oil.

IR(neat,cm⁻¹): 2968,2800,1458,1365,1266,1083,963,771.

¹ H-NMR(300 MHz,CDCl₃,δ ppm):1.04(3H,t,J=7.1 Hz),1.23(9H,s),2.50(2H,q,J=7.1 Hz),3.09(2H,dd,J=6.3 Hz,1.4 Hz),3.17 (2H,dd,J=7.3Hz,1.3 Hz),3.53(2H,s),3.68(2H,s),5.64(1H, dt,J=15.9 Hz,1.4Hz),6.01(1H,dt,J=15.6 Hz,7.3 Hz), 6.07(1H, dt,J=15.9 Hz,6.3Hz),6.42(1H,d,J=15.6 Hz),7.13(1H,dd,J=2.5 Hz,1.3 Hz),7.17-7.28(6H,m).

Compound of Example 66 was obtained by performing the same reaction asin Example 65 except that (E)-3-(3-thienyl)-2-propenylamine [see Chem.Lett., 1733(1984)] was used instead of the starting compound,S-[(E)-3-(3-thienyl)-2-propenyl] thio-acatate.

EXAMPLE 66(E,E)-N-ethyl-N-(6,6-dimethyl-2-hepten-4-ynyl)-3-[3(3-thienyl)-2-propenylaminomethyl]benzylamine

IR(neat,cm⁻¹): 2968,2932,2806,1458,1365,966,768.

¹ H-NMR(300 MHz,CDCl₃,δ ppm):1.07(3H,t,J=7.2 Hz),1.24(9H,s),2.55(2H,q,J=7.2 Hz),2.60(1H,br.s),3.13(2H,dd,J=6.7 Hz,1.5Hz),3.44(2H,d,J=5.7 Hz),3.60(2H,s),3.88(2H,s), 5.65(1H,dt,J=16.0 Hz,1.5Hz),6.08(1H,dt,J=16.0 Hz,6.7 Hz), 6.18(1H,dt,J=15.6 Hz,5.7Hz),6.57(1H,d,J=15.6 Hz),7.14 (1H,dd,J=2.6Hz,1.1Hz),7.20-7.27(3H,m),7.28(2H,d,J=1.1 Hz),7.35(1H,br.s).

EXAMPLE 67 Production of(E)-ethyl-N-(6,6-dimethyl-2-hepten-4-ynyl)-3-[3-(3-thienyloxy)propoxy]benzylamine

49 mg of 3-(3-thienyloxy)propanol [synthesized by heating 1,3-propandioland 3-bromothiophene in the s presence of sodium, copper(I) iodide andcopper(I) oxide at 150° C. for 20 hours] was dissolved in 1 ml of ethylacetate, and 26 μl of methanesulfonyl chloride and 65 μl oftriethylamine were added. The mixture was stirred at room temperaturefor 30 minutes, and the precipitate was removed by filtration, then thesolvent was evaporated under reduced pressure. The residue was added toa dimethylformamide solution (0.5 ml) of phenolate prepared from 80 mgof N-ethyl-N-(6,6-dimethyl-2-hepten-4-ynyl)-3-hydroxybenzylamine and11.8 mg of 60% oily sodium hydride, and the mixture was stirred in thepresence of 48 mg of potassium iodide at room temperature for 20 hours.Ethyl ether and water were added to the reaction solution and theorganic layer was collected, washed with a saturated aqueous solution ofsodium chloride, then dried over anhydrous magnesium sulfate. Thedesiccant was separated by filtration, and the solvent was evaporatedunder reduced pressure. The residue was purified by medium-pressureliquid chromatography [silica gel column, hexane/ethylacetate=20/1→15/1] to give 97 mg (yield 76%) of the captioned compoundas a colorless oil.

IR(neat,cm⁻¹): 2968,1548,1458,1377,1263,1236,1179,1155, 1062,753.

¹ H-NMR(300 MHz,CDCl₃,δ ppm):1.03(3H,t,J=7.1 Hz),1.24(9H,s),2.25(2H,q,J=6.2 Hz),2.45(2H,q,J=7.1 Hz),3.09(2H,dd,J=6.3 Hz,1.6Hz),3.52(2H,s),4.14(2H,t,J=6.2 Hz),4.15(2H,t, J=6.2Hz),5.64(1H,dt,J=15.9 Hz,1.6 Hz),6.07(1H,dt,J=15.9 Hz,6.3Hz),6.27(1H,dd,J=3.1 Hz,1.7 Hz),6.76(1H,dd,J=5.1 Hz,1.7Hz),6.74-6.78(1H,m),6.88-6.91(2H,m),7.17(1H,dd, J=5.1 Hz,3.1Hz),7.l9(1H,t,J=7.8 Hz).

EXAMPLE 68 Production of (E)-3-(3-thienyl)-2-propenyl(E)-3-(N-ethyl-6,6-dimethyl-2-hepten-4-ynylaminomethyl)benzoate

100 mg of methyl(E)-3-(N-ethyl-6,6-dimethyl-2-hepten-4-ynylaminomethyl)benzoate wasdissolved in 5 ml of methanol, and 20 ml of 1N hydrochloric acid wasadded. The mixture was refluxed for 3 hours, and the solvent wasevaporated under reduced pressure. The residual carboxylic acid wasdissolved in 5 ml of chloroform, and to this solution, a drop ofdimethylformamide and 2 ml of thionyl chloride were added. The mixturewas then refluxed for 10 minutes, and the solvent was evaporated underreduced pressure. The residual acid chloride was dissolved in 5 ml ofdioxane, and 224 mg of (E)-3-(3-thienyl)-2-propen-1-ol and 1.1 g ofpotassium carbonate were added. The mixture was then stirred overnightat room temperature. The solvent was evaporated under reduced pressure,and ethyl acetate and water were added to the residue to extract it. Theorganic layer was separated, washed with a saturated aqueous solution ofsodium chloride, and dried over anhydrous magnesium sulfate. Thedesiccant was separated by filtration, and the solvent was evaporatedunder reduced pressure. The residue was purified by medium-pressureliquid chromatography [silica gel column, hexane/ethyl acetate 7/1→5/1]to give 290 mg (yield 43%) of the captioned compound as a colorless oil.

IR(neat,cm⁻¹): 2968,1725,1458,1365,1275,1194,1107,966, 747.

¹ H-NMR(300 MHz,CDCl₃,δ ppm):1.04(3H,t,J=7.1 Hz),1.23(9H,s),2.49(2H,q,J=7.1 Hz),3.09(2H,dd,J=6.3 Hz,1.4 Hz),3.60(2H,s),4.94(2H,dd,J=6.3 Hz,1.6 Hz),5.65(1H,dt,J=15.9 Hz, 1.4Hz),6.07(1H,dt,J=15.9 Hz,6.3 Hz),6.26(1H,dt,J=15.4 Hz, 6.3Hz),6.75(1H,d,J=15.4 Hz),7.21-7.29(3H,m),7.38(1H,t, J=7.5Hz),7.56(1H,d,J=7.5 Hz),7.94(1H,dt,J=7.5 Hz,1.3 Hz), 7.80-7.98(1H,m).

EXAMPLE 69 Production of(E,E)-N-methyl-N-(6,6-dimethyl-2-hepten-4-ynyl)-3-[4-(1-imidazolyl)-2-butenyloxy]benzylamine

50 mg of(E,E)-N-methyl-N-(6,6-dimethyl-2-hepten-4-ynyl)-3-(4-chloro-2-butenyloxy)benzylaminewas dissolved in 0.5 ml of dimethylformamide, and 30 mg of imidazole wasadded. The mixture was heated at 80° C. for 1 hour. The solvent wasevaporated under reduced pressure, and ethyl acetate and water wereadded to the residue to extract it. The organic layer was separated,washed with a saturated aqueous solution of sodium chloride, and driedover anhydrous magnesium sulfate. The desiccant was separated byfiltration, and the solvent was evaporated under reduced pressure. Theresidue was purified by silica gel column chromatography [ethylacetate→ethyl acetate/methanol=10/1] to give 27 mg (yield 53 %) of thecaptioned compound as a pale yellow oil.

IR(neat,cm⁻¹): 2968, 2788, 1587, 1509, 1491, 1455, 1365, 1230, 1026,969.

¹ H-NMR(300 MHz, CDCl₃, δppm):1.24(9H,s),2.18(3H,s),3.03 (2H,dd,J=6.5Hz,1.5 Hz),3.45(2H,s),4.53-4.55(2H,m),4.58-4.61(2H,m)5.65(1H,dt,J=15.8Hz,1.5 Hz),5.81-5.89(1H,m), 5.90-6.12(2H,m),6.77(1H,ddd,J=8.2 Hz,2.5Hz,1.1 Hz),6.88-6.92(3H,m),7.08(1H,t,J=1.0 Hz),7.21(1H,t,J=8.2 Hz),7.49(1H,s).

EXAMPLE 70 Production of(E,E)-N'-ethyl-N'-(6,6-dimethyl-2-hepten-4-ynyl)-N-[β-[4-(3-thienyl)-2-thienyl]acryloyl]ethylenediamine

100 mg of (E)-β-[4-(3-thienyl)-2-thienyl]acrylic acid was suspended in 2ml of chloroform, and 0.6 ml of thionyl chloride was added. The mixturewas refluxed for 10 minutes, and the solvent was evaporated underreduced pressure. The residual acid chloride was dissolved in 0.6 ml ofdioxane, and a dioxane solution (1 ml) of 30 mg of(E)-N-ethyl-N-(6,6-dimethyl-2-hepten-4-ynyl)ethylenediamine and 23.1 mgof potassium carbonate were added. The mixture was then stirredovernight at room temperature. The solvent was s evaporated underreduced pressure, and ethyl acetate and water were added to the residueto extract it. The organic layer was separated, washed with a saturatedaqueous solution of sodium chloride, and dried over anhydrous magnesiumsulfate. The desiccant was separated by filtration, and the solvent wasevaporated under reduced pressure. The residue was purified by silicagel column chromatography [methylene chloride→methylenechloride/methanol=50/1] to give 36 mg (yield 59%) of the captionedcompound as a pale yellow powder, m.p. 97°-100° C.

IR(KBr,cm⁻¹): 2968, 1653, 1623, 1206, 966, 750.

¹ H-NMR(300 MHz, CDCl₃, δppm):1.04(3H,t,J=7.1 Hz),1.24(9H,s),1.72(1H,br.s),2.57(2H,q,J=7.1 Hz),2.61(2H,t,J=5.9Hz),3.15(2H,dd,J=6.5 Hz,1.5 Hz),3.43(2H,dt,J=5.9 Hz,5.5Hz),5.64(1H,dt,J=15.9 Hz,1.5 Hz),6.03(1H,dt,J=15.9 Hz, 6.5Hz),6.24(1H,d,J=15.4 Hz),7.30(1H,dd,J=4.9 Hz,1.5 Hz),7.30-7.35(1H,m),7.36(1H,dd,J=4.9 Hz,2.9 Hz),7.38(1H,dd, J=2.9 Hz,1.5Hz),7.40-7.44(1H,m),7.74(1H,d,J=15.4 Hz).

Compounds of Examples 70 to 74 were obtained by performing the samereaction as in Example 70 except that the corresponding carboxylic acidswere used instead of the starting compound,(E)-β-[4-(3-thienyl)-2-thienyl]acrylic acid, which was used in theabove-mentioned reaction.

EXAMPLE 71(E,E)-N'-ethyl-N'-(6,6-dimethyl-2-hepten-4-ynyl)-N-[3-(3-thienyl)cinnamoyl]ethylenediamine

IR(neat,cm⁻¹): 3292, 2974, 2872, 1662, 1626, 1554, 1365, 1263, 777.

¹ H-NMR(300 MHz, CDCl₃, δppm):1.04(3H,t,J=7.1 Hz),1.23(9H,s),2.57(2H,q,J=7.1 Hz),2.63(2H,t,J=5.9 Hz),3.19(2H,dd,J=6.6 Hz,1.5Hz),3.44(2H,q,J=5.9 Hz),5.65(1H,dt,J=15.7 Hz, 1.5 Hz),6.04(1H,dt,J=15.7Hz,6.6 Hz),6.20-6.30(1H,br.s), 6.46(1H,d,J=15.6 Hz),7.40(1H,t,J=7.5Hz),7.40-7.42(2H, m),7.46(1H,dt,J=7.6 Hz,1.6 Hz),7.48(1H,dd,J=2.4 Hz,1.6Hz),7.57(1H,dt,J=7.6 Hz,1.6 Hz),7.66(1H,d,J=15.6 Hz), 7.73(1H,t,J=1.6Hz).

EXAMPLE 72(E)-N'-ethyl-N'-(6,6-dimethyl-2-hepten-4-ynyl)-N-3-(3-thienyl)phenoxyacetyl]ethylenediamine

IR(neat,cm⁻¹): 2972, 1682, 1534, 1442, 1288, 1272, 1184, 1066, 774.

¹ H-NMR(300 MHz, CDCl₃, δppm):0.97(3H,t,J=7.1 Hz),1.21(9H,s),2.50(2H,q,J=7.1 Hz),2.58(2H,t,J=6.1 Hz),3.09(2H,dd,J=6.3 Hz,1.5Hz),3.38(2B,q,J=6.1 Hz),4.45(2H,s),5.65(1H,dt, J=15.9 Hz,1.5Hz),5.95(1H,dt,J=15.9 Hz,6.3 Hz),6.87(1H, ddd,J=8.0 Hz,2.3 Hz,1.0Hz),7.15(1H,dd,J=2.3 Hz,1.8 Hz), 7.19-7.22(1H,br.s),7.25(1H,dt,J=8.0Hz,1.0 Hz),7.34(1H, t,J=8.0 Hz),7.35-7.40(2H,m),7.45(1H,dd,J=2.7 Hz,1.2Hz).

EXAMPLE 73(E)-N'-ethyl-N'-(6,6-dimethyl-2-hepten-4-ynyl)-N-[3-(3-thienyl)phenylthioacetyl]ethylenediamine

IR(neat,cm⁻¹): 3300, 2974, 1662, 1518, 1269, 774.

¹ H-NMR(300 MHz, CDCl₃, δppm):0.88(3H,t,J=7.1 Hz),1.23(9H,s),2.40-2.60(4H,m),3.00(2H,d,J=5.7 Hz),3.20-3.35(2H,m),3.69(2H,s),5.57(1H,d,J=15.8 Hz),5.90(1H,dt,J=15.8 Hz, 5.7Hz),7.23(1H,ddd,J=7.8 Hz,1.4 Hz,1.2 Hz),7.30-7.46(5H,m),7.52-7.54(1H,m).

EXAMPLE 74(E)-N'-ethyl-N'-(6,6-dimethyl-2-hepten-4-ynyl)-N-[3-(3-thienyl)phenylaminoacetyl]ethylenediamine

IR(neat,cm⁻¹): 3346, 2968, 1665, 1608, 1533.

¹ H-NMR(300 MHz, CDCl₃, δppm):0.86(3H,t,J=7.0 Hz),1.24(9H,s),2.45(2H,q,J=7.0 Hz),2.53(2H,t,J=5.9 Hz),3.04(2H,d,J=6.1Hz),3.31-3.37(2H,m),3.86(2H,d,J=3.7 Hz),4.35(1H, br.s),5.57(1H,d,J=15.5Hz),5.88(1H,dt,J=15.5 Hz,6.1 Hz), 6.57(1H,ddd,J=8.5 Hz,2.0 Hz,1.2Hz),6.84(1H,t,J=2.0 Hz), 7.02(1H,dt,J=8.5 Hz,2.0 Hz),7.23(1H,t,J=8.5Hz),7.35(1H, d,J=1.2 Hz),7.35(1H,d,J=2.3 Hz),7.41(1H,dd,J=2.3 Hz,1.2Hz).

EXAMPLE 75 Production of(E,E)-N-[3-[3-(3-thienyl)phenyl]-2-propenyl]-(N'-ethyl-6,6-dimethyl-2-hepten-4-ynylamino)acetamide

100 mg of (E)-N-ethyl-N-(6,6-dimethyl-2-hepten-4-ynyl)glycinehydrochloride was dissolved in 10 ml of methylene chloride, and 34 μl ofmethyl chloroformate and 0.1 ml of triethylamine were added under icecooling. The mixture was stirred for 30 minutes, and a methylenechloride solution(5 ml) of 90 mg of(E)-3-[3-(3-thienyl)phenyl]-2-propenylamine was added, then the mixturewas stirred at room temperature for 2 hours. The solvent was evaporatedunder reduced pressure, and ethyl acetate and water were added to theresidue to extract it. The organic layer was separated, washed with asaturated aqueous solution of sodium chloride, and dried over anhydrousmagnesium sulfate. The desiccant was separated by filtration and thesolvent was evaporated under reduced pressure. The residue was purifiedby medium-pressure liquid chromatography [silica gel column,hexane→hexane/ethyl acetate=5/1] to give 24 mg (yield 17%) of thecaptioned compound as a pale yellow oil.

IR(neat,cm⁻¹): 3370, 2974, 2872, 1677, 1605, 1518, 1458, 1365, 1266,966, 771.

¹ H-NMR(300 MHz, CDCl₃, δppm):1.05(3H,t,J=7.0 Hz),1.22(9H,s),2.68(2H,q,J=7.0 Hz),3.11(2H,s),3.15(2H,dd,J=6.6 Hz, 1.6Hz),4.07-4.12(2H,m),5.64(1H,dt,J=15.9 Hz,1.6 Hz), 6.00(1H,dt,J=15.9Hz,6.6 Hz),6.26(1H,dt,J=15.8 Hz,6.6 Hz), 6.57(1H,dt,J=15.8 Hz,1.5Hz),7.30(1H,dt,J=8.0 Hz,1.8 Hz), 7.35(1H,t,J=8.0Hz),7.30-7.35(3H,m),7.46(1H,dt,J=8.0 Hz, 1.8 Hz),7.58(1H,t,J=1.8 Hz).

EXAMPLE 76 Production of(E,E)-N'-ethyl-N'-(6,6-dimethyl-2-hepten-4-ynyl)-N-[3-[3-(3-thienyl)phenyl]-2-propenyl]ethylenediamine

30 mg of (E)-3-(3-thienyl)cinnamaldehyde and 29 mg of(E)-N-ethyl-N-(6,6-dimethyl-2-hepten-4-ynyl)ethylenediamine weredissolved in 1 ml of methanol, and 30 mg of molecular sieves 3A wasadded. The mixture was stirred at room temperature for 2 hours, and thenthe insoluble material was removed by filtration. The solvent wasevaporated under reduced pressure, and the residue was suspended in 1 mlof ethanol. To this suspension, 5.3 mg of sodium borohydride was added,and the mixture was stirred at room temperature for 30 minutes. Thesolvent was evaporated under reduced pressure, and ethyl ether and waterwere added to the residue to extract it. The organic layer wasseparated, washed with a saturated aqueous solution of sodium chloride,and dried over anhydrous magnesium sulfate. The desiccant was separatedby filtration, and the solvent was evaporated under reduced pressure.The residue was purified by medium-pressure liquid chromatography[silica gel column, chloroform/methanol =100/1→40/1] to give 35 mg(yield 63%) of the captioned compound as a pale yellow oil.

IR(neat,cm⁻¹): 2968, 2818, 1458, 1365, 1266, 963, 846, 771.

¹ H-NMR(300 MHz, CDCl₃, δppm):1.02(3H,t,J=7.1 Hz),1.23(9H,s),2.53(2H,q,J=7.1 Hz),2.59(2H,t,J=5.7 Hz),2.72(2H,t,J=5.7Hz),3.12(2H,dd,J=6.6 Hz,1.5 Hz),3.44(2H,dd,J=6.3 Hz, 1.1Hz),5.63(1H,dt,J=15.9 Hz,1.5 Hz),6.05(1H,dt,J=15.9 Hz, 6.6Hz),6.36(1H,dt,J=15.9 Hz,6.3 Hz),6.58(1H,dt,J=15.9 Hz, 1.1Hz),7.32-7.37(2H,m),7.39-7.41(2H,m),7.44-7.47(2H, m),7.59-7.61(1H,m).

Compounds of Examples 77 to 79 were obtained by performing the samereaction as in Example 76 except that the corresponding aldehyde orketone compounds were used instead of the starting compound,(E)-3-(3-thienyl)cinnamaldehyde.

EXAMPLE 77(E)-N'-ethyl-N'-(6,6-dimethyl-2-hepten-4-ynyl)-N-2-[3-(3-thienyl)phenoxy]ethyl)ethylenediamine

IR(neat,cm⁻¹): 3300, 2968, 1602, 1455, 1365, 1284, 756.

¹ H-NMR(300 MHz, CDCl₃, δppm):1.03(3H,t,J=7.1 Hz),1.23(9H,s),1.76(1H,br.s),2.55(2H,q,J=7.1 Hz),2.63(2H,t,J=6.0 Hz),2.78(2H,t,J=6.0Hz),3.06(2H,t,J=5.1 Hz),3.15(2H,dd, J=6.6 Hz,1.5 Hz),5.65(1H,dt,J=15.9Hz,1.5 Hz),6.05(1H,dt, J=15.9 Hz,6.6 Hz),6.86(1H,ddd,J=8.1 Hz,2.4 Hz,0.9Hz),7.15 (1H,t,J=2.4 Hz),7.19(1H,ddd,J=7.5 Hz,2.4 Hz,0.9 Hz),7.30(1H,t,J=8.1 Hz),7.37(2H,d,J=2.2 Hz),7.44(1H,t,J=2.2 Hz).

EXAMPLE 78(E)-N'-ethyl-N'-(6,6-dimethyl-2-hepten-4-ynyl)-N-3-[3-(3-thienyl)phenyl]propyl]ethylenediamine

IR(neat,cm⁻¹): 2968, 2932, 2860, 1458, 774.

¹ H-NMR(300 MHz, CDCl₃, δppm): 0.99(3H,t,J=7.1 Hz),1.23(9H, s),2.08(2Hquint.,J=7.4 Hz),2.54(2H,q,J=7.1 Hz)2.68-2.77(4H,m),2.83-2.88(4H,m),3.12(2H,dd,J=6.5 Hz,1.5 Hz),5.61(1H,dt,J=15.9 Hz,1.5 Hz),5.97(1H,dt,J=15.9 Hz,6.5 Hz),7.15(1H,dd,J=8.0 Hz,1.8 Hz),7.29-7.49(6H,m).

EXAMPLE 79(E,E)-N'-ethyl-N'-(6,6-dimethyl-2-hepten-4-ynyl)-N-4-[3-(3-thienyl)phenyl]-3-buten-2-yl]ethylenediamine

IR(neat,cm⁻¹): 2968, 2812, 1461, 1368, 966.

¹ H-NMR(300 MHz, CDCl₃, δppm):1.01(3H,t,J=7.1 Hz),1.23(9H,s),1.27(3H,d,J=6.7 Hz),2.51(2H,q,J=7.1 Hz),2.56-2.78(4H,m),3.11(2H,dd,J=6.7 Hz,1.5 Hz),3.35(1H,quint.,J=6.8 Hz),5.62(1H,dt,J=15.9 Hz,1.5 Hz),6.04(1H,dt,J=15.9 Hz,6.7 Hz},6.14(1H,dd,J=15.7 Hz,7.7 Hz),6.51(1H,d,J=15.7Hz),7.27-7.36(2H,m),7.37-7.42(2H,m),7.43-7.48(2H,m),7.60(1H, br.s).

EXAMPLE 80 Production of(E,E)-N'-ethyl-N'-(6,6-dimethyl-2-hepten-4-ynyl)-N-methyl-N-[3-[3-(3-thienyl)phenyl]-2-propenyl]ethylenediamine

12 mg of(E,E)-N'-ethyl-N'-(6,6-dimethyl-2-hepten-4-ynyl)-N-[3-[3-(3-thienyl)phenyl]-2-propenyl]ethylenediaminewas dissolved in 0.5 ml of ethanol, and 5 μl of 35% formalin was added.The mixture was stirred at room temperature for 5 minutes, and 2 mg ofsodium cyanoborohydride was added. The mixture was then stirred for 1hour, and acidified with 1N hydrochloric acid. The solvent wasevaporated under reduced pressure, and chloroform and water were addedto the residue to extract it. The organic layer was separated, washedwith a saturated aqueous solution of sodium chloride, and dried overanhydrous magnesium sulfate. The desiccant was separated by filtration,and the solvent was evaporated under reduced pressure. The residue waspurified by medium-pressure liquid chromatography [silica gel column,chloroform/methanol=100/1→50/1→10/1] to give 4.1 mg (yield 34%) of thecaptioned compound as a pale yellow oil.

IR(neat,cm⁻¹): 2974, 2800, 1458, 1365, 1269, 966, 771.

¹ H-NMR(300 MHz, CDCl₃, δppm):1.03(3H,t,J=7.1 Hz),1.23(9H,s),2.30(3H,s),2.52-2.60(6H,m),3.16(2H,d,J=6.7 Hz),3.22 (2H,d,J=6.5Hz),5.62(1H,dt,J=15.9 Hz,1.5 Hz),6.06(1H,dt, J=15.9 Hz,6.7Hz),6.33(1H,dt,J=15.9 Hz,6.5 Hz),6.56(1H,d, J=15.9Hz),7.29-7.37(2H,m),7.39(2H,d,J=1.8 Hz),7.45-7.48(2H,m),7.59-7.60(1H,m).

Compounds of Examples 81 and 82 were obtained by performing the samereaction as in Example 80 except that(E)-N'-ethyl-N'-(6,6-dimethyl-2-hepten-4-ynyl)-N-[2-[3-(3-thienyl)phenoxy]ethyl]ethylenediamineor acetaldehyde was used instead of the starting compound, (E,E)-N'-ethyl-N'-(6,6-dimethyl-2-hepten-4-ynyl)-N-[3-[3-(3-thienyl)phenyl]-2-propenyl]ethylenedi-amineor formalin, which was used in the above-mentioned reaction.

EXAMPLE 81(E)-N'-ethyl-N'-(6,6-dimethyl-2-hepten-4-ynyl)-N-methyl-N-[2-[3-(3-thienyl)phenoxy]ethyl]ethylenediamine

IR(neat,cm⁻¹): 2968, 1605, 1455, 1287, 1221, 1038, 771.

¹ H-NMR(300 MHz, CDCl₃, δppm):1.03(3H,t,J=7.1 Hz),1.23(9H,s),2.37(3H,s),2.56(2H,q,J=7.1 Hz),2.61(4H,s),2.86(2H,t, J=5.7Hz),3.17(2H,dd,J=6.6 Hz,1.2 Hz),4.12(2H,t,J=5.7 Hz), 5.62(1H,dt,J=15.9Hz,1.2 Hz),6.05(1H,dt,J=15.9 Hz,6.6 Hz), 6.84(1H,ddd,J=8.4 Hz,2.4 Hz,0.9Hz),7.14(1H,dd,J=2.7 Hz, 2.4 Hz),7.l8(1H,ddd,J=7.5 Hz,1.4 Hz,1.0Hz),7.30(1H,t,J=7.8 Hz),7.37(2H,d,J=2.2 Hz),7.44(1H,t,J=2.2 Hz).

EXAMPLE 82(E,E)-N,N'-diethyl-N'-(6,6-dimethyl-2-hepten-4-ynyl)-N-[3-[3-(3-thienyl)phenyl]-2-propenyl]ethylenediamine

IR(neat,cm⁻¹): 2968, 2926, 2866, 2806, 1365, 966, 771.

¹ H-NMR(300 MHz, CDCl₃, δppm):1.02(3H,t,J=7.2 Hz),1.08(3H,t, J=7.2Hz),1.23(9H,s),2.53(2H,q,J=7.2 Hz),2.60(2H,q,J=7.2Hz),2.58-2.62(4H,m),3.14(2H,dd,J=6.6 Hz,1.5 Hz),3.30 (2H,d,J=6.6Hz),5.62(1H,dt,J=15.9 Hz,1.5 Hz),6.05(1H,dt, J=15.9 Hz,6.6Hz),6.33(1H,dt,J=15.9 Hz,6.6 Hz),6.56(1H,d, J=15.9Hz),7.31-7.39(4H,m),7.44-7.47(2H,m),7.59(1H, br.s).

EXAMPLE 83 Production of(E,E,E)-N-ethyl-N-(6,6-dimethyl-2-hepten-4-ynyl)-3-5-(3-thienyl)-3-oxo-1,4-pentadienyl]benzylamine

10 mg of (E)-4-(3-thienyl)-3-buten-2-one was dissolved in 1.5 ml ofethanol, and 22 mg of(E)-N-ethyl-N-(6,6-dimethyl-2-hepten-4-ynyl)-3-formylbenzylamine and 4mg of sodium methoxide were added. The mixture was refluxed for hour,and the solvent was evaporated under reduced pressure, then ethylacetate and water were added to the residue to extract it. The organiclayer was separated, washed with a saturated s aqueous solution ofsodium chloride, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure, and the residue was purified bymedium-pressure liquid chromatography [silica gel column, hexane/ethylacetate=3/1→methylene chloride/methanol=70/1] to give 13 mg (yield 42%)of the captioned compound as a pale yellow oil.

IR(neat,cm⁻¹): 2968, 1656, 1623, 1458, 1320, 1266, 1185, 1095, 981, 756.

¹ H-NMR(300 MHz, CDCl₃, δppm):1.06(3H,t,J=5.3 Hz),1.24(9H,s),2.50(2H,q,J=5.3 Hz),3.11(2H,dd,J=6.3 Hz,1.5 Hz),3.59(2H,s),5.65(1H,dt,J=15.9 Hz,1.5 Hz),6.05(1H,dt,J=15.9 Hz, 6.3Hz),6.95(1H,d,J=15.8 Hz),7.05(1H,d,J=17.2 Hz),7.337.42(4H,m),7.49(1H,dd,J=4.2 Hz,1.7 Hz),7.60(2H,s),7.72 (1H,d,J=15.8Hz),7.74(1H,d,J=17.2 Hz).

EXAMPLE 84 Production of(E,E)-N-ethyl-N-(6,6-dimethyl-2-hepten-4-ynyl)-6-3-(3-thienyl)phenyl)-4-oxo-5-hexenylamine

A 1M tetrahydrofuran solution (0.6 ml) of lithiumbis-(trimethylsilyl)amide was added to 1 ml of tetrahydrofuran under anargon atmosphere, and the mixture was cooled to -78° C. To this solutionwere added, dropwise with stirring, a tetrahydrofuran solution (2 ml) of125 mg of(E)-N-ethyl-N-(6,6-dimethyl-2-hepten-4-ynyl)-4-oxo-pentylamine, followedby a tetrahydrofuran solution (2 ml) of 94 mg of3-(3-thienyl)benzaldehyde. The mixture was stirred at -78° C. for 1hour, and then at 0° C. for 1 hour. The reaction mixture was neutralizedwith acetic acid, and ethyl acetate and water were added to extract it.The organic layer was separated, washed with a saturated aqueoussolution of sodium chloride, and dried over anhydrous magnesium sulfate.The desiccant was separated by filtration, and the solvent wasevaporated under reduced pressure. The residue was purified by silicagel column chromatography [ethyl acetate→ethyl acetate/methanol=20/1] togive 78 mg (yield 40%) of (E)-N-ethyl-N-(6,6-dimethyl-2-hepten-4-ynyl)-6-hydroxy-4-oxo-6-[3-(3-thienyl)phenyl]hexenylamine.

The resulting alcohol compound (68 mg) was dissolved in 3 ml ofmethylene chloride, and 40 μl of methanesulfonyl chloride and 0.2 ml oftriethylamine were added. The mixture was stirred at room temperaturefor 5 hours, and the solvent was evaporated. The residue was worked upin a customary manner, and then purified by silica gel columnchromatography [hexane/ethyl acetate=1/1] to give 20 mg (yield 30%) ofthe captioned compound as a pale yellow oil.

IR(neat,cm⁻¹): 2974, 1692, 1668, 1611, 1458, 1365, 1266, 1200, 1173,1095, 1053, 901, 774.

¹ H-NMR(300 MHz, CDCl₃, δppm):1.01(3H,t,J=7.2 Hz),1.23(9H,s),1.83(2H,q,J=7.2 Hz),1.48(2H,t,J=7.2 Hz),2.51(2H,q,J=7.2Hz),2.72(2H,t,J=7.2 Hz),3.11(2H,dd,J=6.3 Hz,1.5 Hz), 5.64(1H,dt,J=15.9Hz,1.5 Hz),6.04(1H,dt,J=15.9 Hz,6.3 Hz), 6.79(1H,d,J=16.5Hz),7.38-7.64(6H,m),7.76(1H,t,J=2.1 Hz).

EXAMPLE 85 Production of(E)-N-[3-(3-thienyl)benzyl]-4-(N'-ethyl-6,6-dimethyl-2-hepten-4-ynylamino)crotonamide

100 mg of 4-(N-ethyl-6,6-dimethyl-2-hepten-4-ynylamino)crotonic acid[synthesized by condensing ethyl 4-bromocrotonate withN-ethyl-6,6-dimethyl-2-hepten-4-ynylamine in the presence of base, andsubsequently hydrolizing it with alkaline]hydrochloride was suspended in2 ml of chloroform, and 0.1 ml of thionyl chloride was added. Themixture was stirred at 50 ° C. for 30 minutes, and the solvent wasevaporated under reduced pressure, then the residue was dissolved in 15ml of dioxane. To this solution, 73 mg of 3-(3-thienyl)benzylamine and140 mg of potassium carbonate were added, and the mixture was stirredovernight at room temperature. The solvent was evaporated, and ethylacetate and water were added to the residue to extract it. The organiclayer was separated, washed with a saturated aqueous solution of sodiumchloride, and dried over anhydrous magnesium sulfate. The desiccant wasseparated by filtration, and the solvent was evaporated under reducedpressure. The residue was purified by medium-pressure liquidchromatography [silica gel column, chloroform→chloroform/methanol=50/1]to give 64 mg (yield 37%) of the captioned compound as a pale yellowoil.

IR(neat,cm⁻¹): 3286, 2968, 2926, 1674, 1623, 1548, 1365, 777.

¹ H-NMR(300 MHz, CDCl₃, δppm):1.04(3H,t,J=7.1 Hz),1.23(9H,s),2.50(2H,q,J=7.1 Hz),3.10(2H,dd,J=6.3 Hz,1.4 Hz),3.19 (2H,dd,J=5.7Hz,1.4 Hz),4.55(2H,d,J=5.9 Hz),5.63(1H,dt,J=15.4 Hz,1.4Hz),5.79(1H,t,J=5.9 Hz),5.95-6.06(2H,m),6.87 (1H,dt,J=15.3 Hz,5.7Hz),7.23(1H,dt,J=8.1 Hz,2.4 Hz),7.37 (1H,t,J=8.1Hz),7.37-7.41(2H,m),7.45(1H,dd,J=3.0 Hz,1.8 Hz),7.49-7.54(2H,m).

EXAMPLE 86 Production of(E)-N-3-(N'-ethyl-6,6-dimethyl-2-hepten-4-ynylaminomethyl)phenyl]-3-thienylmethoxyacetamide

30 mg of 3-thienylmethoxyacetic acid was dissolved in 1 ml of methylenechloride, and 24 mg of 1-hydroxybenzotriazole and 31 mg of1-(3-dimethylaminopropyl)-3-ethylcarbodiimide were added. The mixturewas stirred at room temperature for 20 minutes and then a methylenechloride solution (1 ml) of 43 mg of(E)-N-ethyl-N-(6,6-dimethyl-2-hepten-4-ynyl)-3-aminobenzylamine wasadded. The mixture was stirred at room temperature for 2 hours, and thendiluted with methylene chloride. The reaction mixture was washed with asaturated aqueous solution of sodium chloride, and dried over anhydrousmagnesium sulfate. The desiccant was separated by filtration, and thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography [hexane/ethyl acetate=5/1→2/1] togive 61 mg (yield 90%) of the captioned compound as a colorless oil.

IR(neat,cm⁻¹): 3400, 2974, 2932, 2872, 286, 1692, 1614, 1599, 1539,1494, 1446, 1365, 1341, 1311, 1266, 1227, 1158, 1104, 963, 786, 696.

¹ H-NMR(300 MHz, CDCl₃, δppm):1.04(3H,t,J=7.2 Hz),1.24(9H,s),2.50(2H,q,J=7.2 Hz),3.09(2H,dd,J=6.3 Hz,1.5 Hz),3.54(2H,s),4.08(2H,s),4.68(2H,s),5.64(1H,dt,J=15.9 Hz,1.5Hz),6.07(1H,dt,J=15.9 Hz,6.3 Hz),7.09(1H,d.J=7.8 Hz), 7.12(1H,dd,J=5.1Hz,1.5 Hz),7.20-7.58(5H,m),8.26(1H, br.s).

Compounds of Examples 87 to 89 were obtained by performing the samereaction as in Example 86 except that the corresponding carboxylic acidderivatives and amine derivatives were used instead of the startingcompounds, 3-thienylmethoxyacetic acid and(E)-N-ethyl-N-(6,6-dimethyl-2-hepten-4-ynyl)-3-aminobenzylamine, whichwere used in the above-mentioned reaction.

EXAMPLE 87(E)-N-2-(3-thienyl)ethyl]-3-(N'-ethyl-6,6-dimethyl-2-hepten-4-ynylaminomethyl)phenylacetamide

IR(neat,cm⁻¹): 3275, 2950, 1640, 1550, 1440, 1360, 1260, 770.

¹ H-NMR(300 MHz, CDCl₃, δppm):1.03(3H,t,J=7.0 Hz),1.23(9H,s),2.49(2H,q,J=7.0 Hz),2.75(2H,t,J=6.8 Hz),3.07(2H,dd,J=6.3 Hz,1.8Hz),3.45(2H,q,J=6.8 Hz),3.53(4H,s),5.34-5.42 (1H,m),5.64(1H,dt,J=15.9Hz,1.4 Hz),6.05(1H,dt,J=15.9 Hz, 6.3 Hz),6.79-7.29(7H,m).

EXAMPLE 88(E,E)-N-3-(N'-ethyl-6,6-dimethyl-2-hepten-4-ynyl-aminomethyl)benzyl]-β-(3-thienyl)acrylamide

IR(neat,cm⁻¹): 2974, 1626, 1554, 1281, 786, 756.

¹ H-NMR(300 MHz, CDCl₃, δppm):1.04(3H,t,J=7.0 Hz),1.23(9H,s),2.51(2H,q,J=7.0 Hz),3.10(2H,dd,J=6.3 Hz,1.4 Hz),3.55(2H,s),4.56(2H,d,J=5.6 Hz),5.64(1H,dt,J=15.4 Hz,1.9 Hz),5.85-5.92(1H,m),6.06(1H,dt,J=15.9 Hz,6.3 Hz),6.25(1H,d, J=15.7Hz),7.18-7.33(6H,m),7.43-7.45(1H,m),7.66(1H,d,J=15.2 Hz).

EXAMPLE 89(E,E)-N-(3-thienylmethyl)-β-3-(N'-ethyl-6,6-dimethyl-2-hepten-4-ynylaminomethyl)cinnamamide

IR(neat,cm⁻¹): 3280, 2968, 2926, 2866, 2806, 1662, 1626, 1554,

¹ H-NMR(300 MHz, CDCl₃, δppm):1.03(3H,t,J=6.6 Hz),1.23(9H,s),2.50(2H,q,J=6.6 Hz),3.09(2H,dd,J=6.8 Hz,1.9 Hz),3.56(2H,s),4.59(2H,d,J=5.6 Hz),5.60(1H,dt,J=15.8 Hz,1.9 Hz), 5.86(1H,t,J=5.6Hz),6.08(1H,dt,J=15.8 Hz,6.8 Hz),6.40(1H, d,J=15.7 Hz),7.08(1H,dd,J=5.3Hz,1.2 Hz),7.20(1H,m),7.28-7.38(4H,m),7.48(1H,s),7.65(1H,d,J=15.7 Hz).

EXAMPLE 90 Production of(E,E)-N-ethyl-N-(6-methoxy-6-methyl-2-hepten-4-ynyl)-5-3-(3-thienylmethoxy)-1-propenyl]-2-furylmethylaminehydrochloride

123 mg of(E,E)-N-ethyl-N-(6-methoxy-6-methyl-2-hepten-4-)-5-(3-hydroxy-1-propenyl)-2-furylmethylamineand 69 mg of 3-bromomethylthiophene were dissolved in 3 ml ofdimethylform-amide, and 16 mg of 60% oily sodium hydride was added underice cooling. The mixture was stirred at this temperature for 3 hours,and then ethyl ether and water were added. The organic layer wasseparated, washed with a saturated aqueous solution of sodium chloride,and dried over anhydrous magnesium sulfate. The desiccant was separatedby filtration, and the solvent was evaporated under reduced pressure.The residue was purified by silica gel column chromatography[hexane/ethyl acetate=3/1] to give 78 mg (yield 49%) of the captionedfree base as a pale yellow oil. The resulting free base was treated by ahydrogen chloride-ethyl ether solution, and recrystallized from amixture of ethyl acetate and ethyl ether to give the captioned compound(m.p. 100°-102 ° C.) as a colorless crystalline powder.

IR(KBr,cm⁻¹): 2608, 1167, 1119, 1074, 966.

¹ H-NMR(300 MHz, CDCl₃, δppm):1.47(6H,s),1.54(3H,t,J=7.2Hz),2.92-3.16(2H,m),3.35(3H,s),3.62(2H,d,J=7.4 Hz), 4.17(2H,dd,J=1.5Hz,5.3 Hz),4.24(1H,br.s),4.59(1H,s), 5.91(1H,d,J=15.9Hz),6.21-6.32(2H,m),6.42-6.55(2H,m), 6.65(1H,d,J=3.5Hz),7.10(1H,dd,J=5.0 Hz,1.5 Hz),7.23-7.28(1H,m),7.32(1H,dd,J=5.0 Hz,3.0Hz).

Compounds of Examples 91 to 95 were obtained by performing the samereaction as in Example 90 except that the corresponding alcoholderivatives and/or bromoalkyl derivatives were used instead of thestarting s compounds,(E,E)-N-ethyl-N-(6-methoxy-6-methyl-2-hepten-4-)-5-(3-hydroxy-1-propenyl)-2-furylmethylamineand/or 3-bromomethylthiophene, which were used in the above-mentionedreaction.

EXAMPLE 91(E,E)-N-ethyl-N-(6-methoxy-6-methyl-2-hepten-4-ynyl)-5-[3-(3-thienyl)-2-propenyloxymethyl]-2-oxazolylmethylamine

IR(neat,cm⁻¹): 2980, 1248, 1173, 1101, 1074, 966.

¹ H-NMR(300 MHz, CDCl₃, δppm):1.09(3H,t,J=7.1 Hz),1.46(6H,s),2.58(2H,q,J=7.1 Hz),3.23(2H,dd,J=6.2 Hz,1.5 Hz),3.35(3H,s),3.78(2H,s),4.16(2H,dd,J=6.4 Hz,1.5 Hz),4.53(2H,s),5.72(1H,dt,J=15.9 Hz,1.5 Hz),6.08-6.20(2H,m),6.63(1H, d,J=15.9Hz),6.98(1H,s),7.18(1H,dd,J=2.7 Hz,1.5 Hz),7.21 (1H,dd,J=5.4 Hz,1.5Hz),7.28(1H,dd,J=5.4 Hz,3.0 Hz)

EXAMPLE 92(E,E)-N-ethyl-N-(6-methoxy-6-methyl-2-hepten-4-ynyl)-2-[3-(3-thienyl)-2-propenyloxymethyl]-4-thiazolylmethylamine

IR(neat,cm⁻¹): 2980, 2926, 2824, 1248, 1173, 1149, 1107, 1074, 966.

¹ H-NMR(300 MHz, CDCl₃, δppm):1.09(3H,t,J=7.1 Hz),1.46(6H,s),2.57(2H,q,J=7.1 Hz),3.19(2H,dd,J=6.3 Hz,1.8 Hz),3.35(3H,s),3.73(2H,s),4.26(2H,dd,J=6.3 Hz,1.5 Hz),4.81(2H,s),5.69(1H,dt,J=15.6 Hz,1.8 Hz),6.16(1H,dt,J=15.9 Hz, 6.3Hz),6.19(1H,dt,J=15.6 Hz,6.3 Hz),6.66(1H,dt,J=15.9 Hz, 1.5Hz),7.12(1H,s),7.17(1H,dd,J=3.0 Hz,1.2 Hz),7.22(1H, dd,J=5.4 Hz,1.2Hz),7.27(1H,dd,J=5.4 Hz,3.0 Hz).

EXAMPLE 93(E,E)-N-ethyl-N-(6-methoxy-6-methyl-2-hepten-4-ynyl)-3-[3-(3-thienylmethoxy)-1-propenyl]-2-isoxazolylmethylamine

IR(neat,cm⁻¹): 2980, 1440, 1362, 1248, 1173, 1152, 1113, 1074, 966, 780.

¹ H-NMR(30 ppm):1.08(3H,t,J=7.1 Hz),1.46(6H, s),2.55(2H,q,J=7.1Hz),3.17(2H,dd,J=6.3 Hz,1.5 Hz),3.36 (3H,s),3.75(2H,s),4.20(2H,dd,J=5.3Hz,1.5 Hz),4.59(2H, s),5.72(1H,dt,J=15.9 Hz,1.5 Hz),6.13(1H,dt,J=15.9Hz, 6.3 Hz),6.24(1H,s),6.40(1H,dt,J=16.1 Hz,5.3 Hz),6.69(1H, dt,J=16.1Hz,1.5 Hz),7.10(1H,dd,J=4.9 Hz,1.3 Hz),7.21-7.23 (1H,m),7.32(1H,dd,J=4.9Hz,2.9 Hz).

EXAMPLE 94(E)-N-ethyl-N-(6,6-dimethyl-2-hepten-4-ynyl)-3-[3-(5-oxazolyl)-2-propenyloxymethyl]benzylamine

IR(neat,cm⁻¹): 2974, 1365, 1266, 1110, 960.

¹ H-NMR(300 MHz, CDCl₃, δppm):1.01-1.16(3H,m),1.24(9H,s),2.48-2.65(2H,m),3.05-3.25(2H,m),3.54-3.70(2H,m),4.19 (2H,dd,J=1.5 Hz,5.3Hz),4.57(2H,s),5.66(1H,d,J=15.9 Hz), 6.09(1H,dt,J=15.5 Hz,6.5Hz),6.34(1H,dt,J=15.8 Hz,5.3 Hz), 6.53(1H,d,J=15.8Hz),6.97(1H,s),7.22-7.38(4H,m),7.79 (1H,s).

EXAMPLE 95(E)-N-ethyl-N-(6,6-dimethyl-2-hepten-4-ynyl)-3-2-(3thienyloxy)ethoxymethyl]benzylamine

IR(neat,cm⁻¹): 2968, 2932, 2872, 1548, 1362, 1179, 1110, 753.

¹ H-NMR(300 MHz, CDCl₃, δppm):1.03(3H,t,J=7.3 Hz),1.24(9H,s),2.50(2H,q,J=7.3 Hz),3.09(2H,dd,J=6.3 Hz,1.7 Hz),3.55(2H,s),3.80-3.82(2H,m),4.12-4.15(2H,m),4.61(2H,s), 5.64(1H,dt,J=15.9Hz,1.7 Hz),6.07(1H,dt,J=15.9 Hz,6.3 Hz), 6.26(1H,dd,J=3.0 Hz,1.6Hz),6.79(1H,dd,J=5.3 Hz,1.6 Hz), 7.16(1H,dd,J=5.3 Hz,3.0Hz),7.15-7.31(4H,m).

EXAMPLE 96 Production of(E)-N-ethyl-N-(6,6-dimethyl-2-hepten-4-ynyl)-3-3-(3-thienylmethoxy)-2-oxopropyl]benzylamine

A methylene chloride solution( 0.6 ml) of 25 μl of oxalyl chloride and amethylene chloride solution (1 ml) of 45 mg of dimethylsulfoxide weremixed at -70 ° C., and to this solution, a methylene chloridesolution(1.5 ml) of 61 mg of(E)-N-ethyl-N-(6,6-dimethyl-2-hepten-4-ynyl)-3-[2-hydroxy-3-(3-thienylmethoxy)propyl]benzylaminewas added. After stirring at -70° C. for 1 hour, 0.1 ml of triethylaminewas added, and then the mixture was stirred at this temperature for 5minutes. The solvent was evaporated under reduced pressure, andmethylene chloride and water were added to the residue to extract it.The organic layer was separated, washed with a saturated aqueoussolution of sodium chloride, and dried over anhydrous magnesium sulfate.The desiccant was separated by filtration, and the solvent wasevaporated under reduced pressure. The residue was purified bymedium-pressure liquid chromatography [silica gel column, hexane ethylacetate 4/1] to give 43 mg (yield 70%) of the captioned compound as acolorless oil.

IR(neat,cm⁻¹): 2974, 1731, 1365, 1269, 1134, 1095, 783.

¹ H-NMR(300 MHz, CDCl₃, δppm):1.03(3H,t,J=7.1 Hz),1.24(9H,s),2.49(2H,q,J=7.1 Hz),3.08(2H,dd,J=5.4 Hz,1.3 Hz),3.53(2H,s),3.74(2H,s),4.10(2H,s),5.63(1H,dt,J=15.9 Hz,1.3Hz),6.06(1H,dt,J=15.9 Hz,5.4Hz),7.05-7.07(2H,m),7.16-7.23(5H,m),7.31(1H,dd,J=4.8 Hz,2.9 Hz).

Compound of Example 97 was obtained by performing the same reaction asin Example 96 except thatN-ethyl-N-(6,6-dimethyl-2-hepten-4-ynyl)-2-hydroxy-5-[3-(3-thienyl)phenoxy]pentylaminewas used instead of the starting compound,(E)-N-ethyl-N-(6,6-dimethyl-2-hepten-4-ynyl)-3-[2-hydroxy-3-(3-thienyl-methoxy)propyl]benzylamine,which was used in the above-mentioned reaction.

EXAMPLE 97(E)-N-ethyl-N-(6,6-dimethyl-2-hepten-4-ynyl)-2-oxo-5-[3-(3-thienyl)phenoxy]pentylamine

IR(neat,cm⁻¹): 2968, 1716, 1605, 1584, 1287, 1218, 1185, 771.

¹ H-NMR(300 MHz, CDCl₃, δppm):1.03(3H,t,J=7.1 Hz),1.23(9H,s),2.08(2H,q,J=6.3 Hz),2.54(2H,q,J=7.1 Hz),2.70(2H,t,J=7.1Hz),3.15(2H,dd,J=6.6 Hz,1.5 Hz),3.24(2H,s),5.62(1H, dt,J=15.9 Hz,1.5Hz),6.02(1H,dt,J=15.9 Hz,6.6 Hz),6.81(1H, ddd,J=7.9 Hz,2.3 Hz,1.1Hz),7.12(1H,t,J=2.2 Hz),7.17(1H, dt,J=8.0 Hz,1.4 Hz),7.30(1H,t,J=7.5Hz),7.37(2H,d,J=2.2 Hz),7.45(1H,t,J=2.2 Hz).

EXAMPLE 98 Production of(E)-2-(N-ethyl-6,6-dimethyl-2-hepten-4-ynylamino)ethyl(E)-3-(3-thienyl)cinnamate

100 mg of 3-(3-thienyl)cinnamic acid was dissolved in 2 ml ofchloroform, and 0.3 ml of thionyl chloride was added. The mixture wasstirred at 70 ° C. for 1 hour, and then the solvent was evaporated underreduced pressure. A chloroform solution ( 2 ml) of 100 mg of(E)-2-(N-ethyl-6,6-dimethyl-2-hepten-4-ynylamino)ethanol was added tothe residue, and the mixture was stirred at room temperature for 1 hour.The solvent was evaporated under reduced pressure, and the residue waspurified by medium-pressure liquid chromatography [silica gel column,chloroform→chloroform/methanol=10/1] to give 23 mg (yield 11%) of thecaptioned compound as a colorless oil.

IR(neat,cm⁻¹): 2974, 1713, 1644, 1458, 1365, 1308, 1263, 1167, 981, 960,777.

¹ H-NMR(300 MHz, CDCl₃, δppm):1.05(3H,t,J=7.0 Hz),1.23(9H,s),2.61(2H,q,J=7.0 Hz),2.79(2H,t,J=6.1 Hz),3.21(2H,dd,J=6.6 Hz,1.2Hz),4.28(2H,t,J=6.1 Hz),5.67(1H,dt,J=15.9 Hz, 1.2 Hz),6.06(1H,dt,J=15.9Hz,6.6 Hz),6.50(1H,d,J=16.0 Hz), 7.38-7.47(4H,m),7.48(1H,dd,J=3.0 Hz,1.9Hz),7.61(1H,dt, J=7.0 Hz,1.7 Hz),7.73(1H,d,J=16.0 Hz),7.73(1H,t,J=1.7Hz).

EXAMPLE 99 Production of(E,E)-N-ethyl-N-(6-methoxy-6-methyl-2-hepten-4-ynyl)-4-[3-(3-thienyl)-2-propenoxymethyl]-2-pyridylmethylamine

11.6 mg of 60% oily sodium hydride was suspended in 0.5 ml oftetrahydrofuran at 0 ° C., under a nitrogen atmosphere, and atetrahydrofuran solution( 2 ml) of 87.5 mg of(E)-N-ethyl-N-(6-methoxy-6-methyl-2-hepten-4-ynyl)-4-hydroxymethyl-2-pyridylmethylaminewas added dropwise. The mixture was stirred for 20 minutes, and atetrahydrofuran solution (1 ml) of 50 mg of(E)-3-bromo-1-(3-thienyl)-1-propene was added dropwise. The mixture wasstirred overnight at room temperature, and then ice water and ethylether were added. The organic layer was separated, washed with asaturated aqueous solution of sodium chloride, and dried over anhydrousmagnesium sulfate. The desiccant was separated by filtration, and thesolvent was evaporated under reduced pressure. The residue was purifiedby medium-pressure liquid chromatography [silica gel column,chloroform→chloroform/methanol=20/1] to give 56 mg (yield 46%) of thecaptioned compound as a pale yellow oil.

IR(neat,cm⁻¹): 2980, 2938, 1362, 1248, 1173, 1152, 1113, 1074, 966.

¹ H-NMR(300 MHz, CDCl₃, δppm):1.06(3H,t,J=7.1 Hz),1.45(6H,s),2.57(2H,q,J=7.1 Hz),3.18(2H,dd,J=6.4 Hz,1.5 Hz),3.34(3H,s),3.73(2H,s),4.21(2H,dd,J=6.4 Hz,1.5 Hz),4.57(2H,s),5.69(1H,dd,J=15.7 Hz,1.5 Hz),6.17(1H,dt,J=15.7 Hz,6.4Hz),6.18(1H,dt,J=15.7 Hz,6.4 Hz),6.66(1H,d,J=15.7 Hz), 7.17(1H,dd,J=4.9Hz,1.0 Hz),7.19(1H,d,J=3.0 Hz),7.23(1H, dd,J=5.6 Hz,1.8Hz),7.28(1H,dd,J=4.9 Hz,3.0 Hz),7.43-7.45 (1H,m),8.50(1H,dd,J=5.6 Hz,1.3Hz).

EXAMPLE 100 Production of(E)-N-(6-acetoxy-6-methyl-2,4-heptadiynyl)-5-3-(3-thienyl)-2-propenoxymethyl]-2-furylmethylamine

196 mg of(E)-N-ethyl-N-(6-hydroxy-6-methyl-2,4-heptadiynyl)-5-[3-(3-thienyl)-2-propenyloxymethyl]-2-furylmethylamine[synthesized by condensing the same reaction as in Example 58 using(E)-N-ethyl-N-propargyl-5-[3-(3-thienyl)-2-propenyloxymethyl]-2-furylmethylamineand 1-bromo-3-hydroxy-3-methyl-1-butyne as starting materials]wasdissolved in 2 ml of pyridine, and 106 μl of acetyl chloride and 60 mgof 4-dimethylaminopyridine were added. The solution was stirred at roomtemperature for 24 hours, and then the solvent was evaporated underreduced pressure. Ethyl acetate and water were added to the residue toextract it, and the organic layer separated was washed with water, thendried over anhydrous magnesium sulfate. The desiccant was separated byfiltration, and the solvent was evaporated under reduced pressure. Theresidue was purified by silica gel column chromatography [hexane/ethylacetate=10/1→4/1] to give 51 mg (yield 26%) of the captioned compound asa pale yellow oil.

IR(neat,cm⁻¹): 1746, 1371, 1242, 1197, 1155, 1125, 1056, 1017, 966.

¹ H-NMR(300 MHz, CDCl₃, δppm):1.09(3H,t,J=7.2 Hz),1.67(6H,s),2.03(3H,s),2.59(2H,q,J=7.2 Hz),3.46(3H,s),3.65(2H,s),4.14(2H,dd,J=6.0 Hz,1.2 Hz),4.46(2H,s),6.13(1H,dt,J=15.9 Hz,6.0Hz),6.21(1H,d,J=3.2 Hz),6.26(1H,d,J=3.2 Hz), 6.62(1H,dt,J=15.9 Hz,1.2Hz),7.15(1H,dd,J=3.0 Hz,1.2 Hz), 7.21(1H,dd,J=5.1 Hz,1.2Hz),7.26(1H,dd,J=5.1 Hz,3.0 Hz).

EXAMPLE 101 Production of a powder and capsules containing the compoundof Example 30 as active ingredients

1 g of the compound (hydrochloride) of Example 30, 12 g of lactose, 5.8g of corn starch and 0.2 g of magnesium stearate were mixed uniformly toform a powder containing 1 g of the active ingredient per 20 g.

The powder obtained above was filled in hard gelatin capsules in anamount of 200 mg per capsule to give capsules containing 10 mg of theactive ingredient per capsule.

The following Referential Examples illustrate the general synthesizingmethods of the starting compounds used in the foregoing Examples.

Referential Example 1 Production of(E)-3-[3-(3-bromomethylbenzyloxy)-1-propenyl]thiophene

18 g of 3-thiophenecarboxaldehyde was dissolved in 300 ml of pyridine,and 25 g of malonic acid and 1.8 ml of piperidine were added. Themixture was refluxed for 3 hours, and the solvent was evaporated, thenethyl acetate and water were added to the residue to extract it. Theorganic layer was separated, washed with IN hydrochloric acid, and thesolvent was evaporated. The residue was treated with ethyl ether, andthe precipitate was collected by filtration, then dissolved in 400 ml ofmethanol. 17.5 ml of thionyl chloride was added, and the mixture wasstirred for 30 minutes. The solvent was evaporated, and the residue wasworked up in a customary manner, then purified by silica gel columnchromatography [hexane/ethyl acetate=3/1] to give 16.1 g of methyl(E)-α-(3-thienyl)acrylate as a pale yellow powder.

10 g of the resulting ester compound was dissolved in 200 ml oftetrahydrofuran, and 150 ml of a 1M diisobutylaluminum hydride toluenesolution was added at -40 ° C. The mixture was stirred for 30 minutes,and the solvent was evaporated. The residue was worked up in a customarymanner, and purified by silica gel column chromatography [hexane/ethylacetate=1/1] to give 8.4 g of (E)-3-(3-thienyl)-2-propen-1-ol as a whitepowder.

1.3 g of the resulting alcohol compound and 3.0 g ofα,α'-dibromo-m-xylene were dissolved in 15 ml of dimethylformamide, and400 mg of 60% oily sodium hydride was added at -60° C. The mixture wasstirred at room temperature for 30 minutes, and then the solvent wasevaporated. The residue was worked up in a customary manner, andpurified by silica gel column chromatography [hexane/ethyl acetate=60/1]to give 1.9 g of the captioned compound as a colorless oil.

When the same reactions as in Referential Example 1 are carried outusing (E)-3-(3-chloromethylphenyl)-2-propen-1-ol [synthesized by thesame reaction as in Referential Example 1 using3-hydroxymethylbenzaldehyde, prepared by partial reduction ofisophthalaldehyde, and malonic acid ] or3-(3-thienyl)propanol[synthesized by the catalytic hydrogenation of(E)-3-(3-thienyl)-2-propen-1-ol in the presence of 10% palladium-carboncatalyst in methanol] and/or 3-bromothiophene, α,α'-dichloro-m-xylene3,5-bis(chloromethyl)-1,2,4-oxadiazole[see Tetrahedron, 46,3941(1990)]or 2,6-bis(chloromethyl)pyridine instead of the starting(E)-3-(3-thienyl)-2-propen-1-ol and α,α'-dibromo-m-xylene,(E)-3-[3-(3-chloromethylphenyl)-2-propenyloxymethyl]thiophene,3-[3-(3-chloromethylbenzyloxy)propyl]thiophene(E)-3-chloromethyl-5-[3-(3-thienyl)-2-propenyloxymethyl]-1,2,4-oxadiazoleand (E)-6-chloromethyl-2-[3-(3-thienyl)-2-propenyloxymethyl]pyridine areobtained.

Referential Example 2 Production of (E)-4-(3-thienyl)-3-buten-1-ol

1.0 g of (3-hydroxypropyl)triphenylphosphonium bromide was dissolved in20 ml of tetrahydrofuran, and under ice cooling, 3.4 ml of a 15%n-butyllithiumhexane solution was added. After the mixture was stirredfor 30 minutes, 270 mg of 3-thiophenecarboxaldhyde was added. Themixture was stirred for 30 minutes, and then the solvent was evaporated.The residue was worked up in a customary manner, and purified by silicagel column chromatography [benzene/ethyl acetate=6/1] to give 28 mg(yield 7%) of the captioned compound as a colorless oil.

Referential Example 3 Production of(E,E)-N-methyl-N-(6,6-dimethyl-2-hepten-4-ynyl)-3-(4-chloro-2-butenyloxy)benzylamine

245 mg of(E)-N-methyl-N-(6,6-dimethyl-2-hepten-4-ynyl)-3-hydroxybenzylamine wasdissolved in 5 ml of tetrahydrofuran, and under ice cooling, 40 mg ofoily sodium hydride was added. After the mixture was stirred for 15minutes, a dimethylformamide solution (3ml) of 125 mg of(E)-1,4-dichloro-2-butene was added. The mixture was stirred at roomtemperature for 12 hours, and then the solvent was evaporated. Theresidue was worked up in a customary manner, and purified by silica gelcolumn chromatography [hexane/ethyl acetate=5/1] to give 216 mg of thecaptioned compound as a colorless oil.

Referential Example 4 Production of(E)-N-ethyl-N-(6,6-dimethyl-2-hepten-4-ynyl)-3-formylbenzylamine

440 mg of 3-bromomethylbenzaldehyde [synthesized by brominating3-hydroxymethylbenzaldehyde with phosphorus tribromide ]was dissolved in10 ml of dimethylformamide, and 535 mg of(E)-N-ethyl-6,6-dimethyl-2-hepten-4-ynylamine hydrochloride and 460 mgof potassium carbonate were added. The mixture was stirred overnight atroom temperature, and then the solvent was evaporated. The residue wasworked up in a customary manner, and purified by silica gel columnchromatography [hexane/ethyl acetate=20/1] to give 670 mg of thecaptioned compound as a pale yellow oil.

When the same reactions as in Referential Example 4 are carried outusing methyl 3-bromomethylbenzoate [synthesized by brominating methylm-toluate with N-bromosuccinimide] or α,α'-dichloro-m-xylene instead ofthe starting 3-bromomethylbenzaldehyde, methyl(E)-3-(N-ethyl-6,6-dimethyl-2-hepten-4-ynylaminomethyl)benzoate or(E)-N-ethyl-N-(6,6-dimethyl-2-hepten-4-ynyl)-3-chloromethylbenzylamineis obtained.

Referential Example 5 Production of (E)-4-(3-thienyl)-3-buten-2-one

1.6 g of 3-thiophenecarboxaldehyde was dissolved in 30 ml of acetone,and 20 g of potassium carbonate was added. The mixture was stirredovernight at room temperature. The solvent was evaporated, and theresidue was worked up in a customary manner. The resulting alcoholcompound was dissolved in 10 ml of methylene chloride, and 1.1 ml ofmethanesulfonyl chloride and 2.3 ml of triethylamine were added. Themixture was stirred overnight at room temperature, and then the solventwas evaporated. The residue was worked up in a customary manner, andpurified by silica gel column chromatography [hexane/ethyl acetate=40/1]to give 650 mg of the captioned compound as a pale yellow oil.

Referential Example 6 Production ofS-[(E)-3-(3-thienyl)-2-propenyl]thioacetate

500 mg of (E)-3-(3-thienyl)-2-propen-1-ol was dissolved in 10 ml ofethyl acetate, and 0.3 ml of phosphorus tribromide was added under icecooling. The mixture was stirred for 2 hours. The solvent was sevaporated, and the residue was worked up in a customary manner. Theresulting brominated compound was dissolved in 5 ml ofdimethylformamide, and 650 mg of potassium thioacetate was added underice cooling. The mixture was stirred for 1 hour, and then the solventwas evaporated. The residue was worked up in a customary manner, andpurified by silica gel column chromatography [hexane/ethyl acetate=50/1]to give 679 mg of the captioned compound as a pale yellow oil.

Referential Example 7 Production of 2-(3-thienylmethoxy)ethanol

621 mg of ethylene glycol was dissolved in 1 ml of tetrahydrofuran, and88 mg of 60% oily sodium hydride and 0.5 ml of dimethylformamide wereadded. After the mixture was stirred at room temperature for 5 minutes,a tetrahydrofuran solution(1 ml) of 200 mg of 3-bromomethylthiophene wasadded. The mixture was stirred at 60 ° C. for 2 hours, and then thesolvent was evaporated. The residue was worked up in a customary mannerto give 181 mg of the captioned compound as a pale yellow oil.

Referential Example 8 Production of(E)-N-ethyl-N-(6,6-dimethyl-2-hepten-4-ynyl)ethylenediamine

6.3 g of N-(2-bromoethyl)phthalimide [see Org. Syn. V, 585 was dissolvedin 50 ml of dimethylformamide, and 5.0 g of(E)-N-ethyl-6,6-dimethyl-2-hepten-4-ynylamine hydrochloride and 4.1 9 ofpotassium carbonate were added. The mixture was stirred at 70 ° C. for6.5 hours, and then the solvent was evaporated. The residue was workedup in a customary manner, and purified by silica gel columnchromatography [hexane/ethyl acetate 10/1→4/1], followed by treated withhexane to give 1.7 g of(E)-N-[2-(N'-ethyl-6,6-dimethyl-2-hepten-4-ynylamino)ethyl]phthalimideas a pale yellow powder.

1.5 g of the resulting phthalimide compound was dissolved in 15 ml ofethanol, and 0.23 ml of hydrazine hydrate was added. The mixture wasstirred overnight at room temperature, and then the precipitate wasremoved by filtration. The solvent was evaporated and ethyl acetate andIN hydrochloric acid were added to the residue to extract it. Theaqueous layer was separated, neutralized with potassium carbonate, andthen extracted with ethyl acetate. The extract was worked up in acustomary manner, and the solvent was evaporated to give 1.0 g of thecaptioned compound as a pale yellow oil.

Referential Example 9 Production of(E)-N-ethyl-N-(6,6-dimethyl-2-hepten-4-ynyl)glycine hydrochloride

1.0 g of (E)-N-ethyl-6,6-dimethyl-2-hepten-4-ynylamine hydrochloride wasdissolved in 20 ml of dimethylformamide, and 0.7 g of methylbromoacetate and 1.0 g of potassium carbonate were added. The mixturewas stirred overnight at room temperature, and worked up in a customarymanner. The resulting glycine ester compound was dissolved in a methanolsolution (50 ml) of 0.5 g of sodium hydroxide, and 25 ml of water wasadded. The mixture was stirred at room temperature for 2 hours, and thesolvent was evaporated. The residue was dissolved in water, and thesolution was made weakly acidic with hydrochloric acid, then butanol anda saturated aqueous solution of sodium chloride were added. The organiclayer was separated and the solvent was evaporated, then the residue wasdissolved in a 10% hydrogenchloridemethanol solution. The solvent wasre-evaporated, and the residue was treated with hexane to give 1.36 g ofthe captioned compound as a pale yellow powder.

Referential Example 10 Production of(E)-2-(N-ethyl-6,6-dimethyl-2-hepten-4-ynylamino)ethanol

1.3 g of (E)-N-ethyl-N-(6,6-dimethyl-2-hepten-4-ynyl)glycine methylester, obtained in Referential Example 9, was dissolved in 30 ml ofethyl ether, and 0.2 g of lithium aluminum hydride was added under icecooling with stirring. The mixture was stirred for 1 hour, and thenwater was added. After the mixture was stirred for 1 hour, theprecipitate was removed by filtration. The organic layer was separated,and the solvent was evaporated to give 1.0 g of the captioned compoundas a pale yellow oil.

Referential Example 11 Production of(E)-β-4-(3-thienyl)-2-thienylacrylic acid

517 mg of 4-(3-thienyl)-2-thienylcarboxaldehyde, 552 mg of malonic acidand 41 μl of piperidine were dissolved in 30 ml of pyridine, and themixture was refluxed for 5.5 hours. The solvent was evaporated, and theresidue was dissolved in water. The resulting solution was acidifiedwith hydrochloric acid, and extracted with ethyl acetate, then theextract was worked up in a customary manner to give 508 mg of thecaptioned compound as a pale yellow powder.

When the same reaction as in Referential Example 11 is carried out using3-(3-thienyl)benzaldehyde instead of the starting(4-(3-thienyl)-2-thienylcarboxyaldehyde, (E)-3-(3-thienyl)cinnamic acidis obtained.

Referential Example 12 Production of 3-(3-thienyl)phenoxyacetic acid

0.5 g of 3-bromophenol and 0.33 ml of ethyl bromoacetate were dissolvedin 4 ml of dimethylformamide, and 0.4 g of potassium carbonate wasadded. The mixture was stirred at 65°-70° C. for 3.5 hours. The solventwas evaporated, and the residue was worked up in a customary manner togive 0.6 g of ethyl 3-bromophenoxyacetate as a colorless oil.

2.6 g of the resulting ether compound, 5.3 g oftri-n-butyl(3-thienyl)tin and 20 mg oftetrakis(triphenhylphosphine)paladium were dissolved in 10 ml of xylene,and the mixture was refluxed for 5.5 hours. A 25% aqueous solution ofpotassium fluoride was added to the solution, and then the precipitatewas removed by filtration. The organic layer separated was worked up ina customary manner, and the product was purified by silica gel columnchromatography [hexane/ethyl acetate=20/1→15/1] to give 1.7 g of ethyl3-(3-thienyl)phenoxyacetate as a white powder.

0.7 g of the resulting thienyl compound was dissolved in 20 ml ofethanol, and 1 ml of a 10% aqueous solution of sodium hydroxide wasadded. The mixture was stirred at 60° C. for 10 minutes, and acidifiedwith hydrochloric acid, then the solvent was evaporated. The residue wasworked up in a customary manner to give 0.6 g of the captioned compoundas a white powder.

When the same reactions as in Referential Example 12 are carried outusing 3-bromothiophenol or 3-bromoaniline instead of the starting3-bromophenol, 3-(3-thienyl)phenylthioacetic acid and3-(3-thienyl)phenylaminoacetic acid are obtained.

Referential Example 13 Production of (E)-3-(3-thienyl)cinnamaldehyde

1.0 g of 3-(3-thienyl)benzaldehyde, 0.5 g of cyanoacetic acid, 15 mg ofammonium acetate and 1 ml of pyridine were dissolved in 1.5 ml ofxylene, and the mixture was refluxed for 5.5 hours. The solvent wasevaporated, and the residue was dissolved in a mixture of ethyl etherand water, then the resulting solution was acidified with dilutedhydrochloric acid. The organic layer separated was worked up in acustomary manner, and the product purified by medium-pressure liquidchromatography [silica gel column, hexane/ethyl acetate=7/1→5/1] to give0.4 g of (E)-3-(3-thienyl)cinnamonitrile as a white powder.

0.4 g of the resulting nitrile compound was dissolved in 2 ml oftoluene, and under cooling at -78° C., a 1.0M toluene solution(2 ml) ofdiisobutylaluminum hydride was added. The mixture was stirred at thistemperature for 20 minutes, and then poured into ice-cold water. Theresulting solution was acidified with a small amount of a 10% aqueoussolution of sulfuric acid, and extracted with ethyl ether. The extractwas worked up in a customary manner, and purified by medium-pressureliquid chromatography [silica gel column, hexane/ethyl acetate=9/1→7/1]to give 0.2 g of the captioned compound as a pale yellow oil.

Referential Example 14 Production of 3-(3-thienyl)phenoxyacetaldehyde

0.54 g of ethyl 3-(3-thienyl)phenoxyacetate obtained in ReferentialExample 12 was dissolved in 5 ml of tetrahydrofuran, and under icecooling with stirring, 76 mg of lithium aluminum hydride was added. Themixture was stirred for 20 minutes, and the solution was then worked upin a customary manner to give 0.43 g of 2-[3-(3-thienyl)phenoxy]ethanolas a white powder.

The resulting alcohol compound was oxidized in a similar manner to thatdescribed in J. Org. Chem., 43, 2481 (1978) using oxalyl chloride anddimethylsulfoxide to give the captioned compound.

Referential Example 15 Production of 3-[3-(3-thienyl)phenyl]propanal

To a suspension (20 ml) of 0.4 g of lithium aluminum hydride interahydrofuran was added, under ice cooling, a tetrahydrofuran solution(10 ml) of 2.1 g of ethyl (E)-3-(3-thienyl)cinnamate [synthesized by thesame reaction as in Referential Example 12 using ethyl(E)-3-bromocinnamate [see Org. Syn. I, 252] andtri-n-butyl(3-thienyl)tin ]. The mixture was stirred at room temperaturefor 30 minutes, and then refluxed for 30 minutes. The solution wasworked up in a customary manner, and the product was purified bymedium-pressure liquid chromatography [silica gel column, hexane/ethylacetate=5/1→5/2] to give 1.1 g of 3-[3-(3-thienyl)phenyl]-1-propanol asa pale yellow oil.

150 mg of the resulting alcohol compound was dissolved in 5 ml ofchloroform, and 222 mg of pyridinium chlorochromate was added. Themixture was stirred overnight at room temperature, and then the sprecipitate was removed by filtration. The filtrate was Worked up in acustomary manner, and the product was purified by silica gel columnchromatography [hexane/ethyl acetate=5/1] to give 115 mg Of thecaptioned compound as a colorless oil.

Referential Example 16 Production of(E)-4-[3-(3-thienyl)phenyl]-3-buten-2-one

300 mg of 3-(3-thienyl)benzaldehyde was dissolved in 3 ml of acetone,and 441 mg of potassium carbonate was added. The mixture was stirredovernight at s room temperature, and then the solvent was evaporated.The residue was worked up in a customary manner, and purified bymedium-pressure liquid chromatography [hexane/ethyl acetate =3/1]to give1-[3-(3-thienyl)phenyl]-3-oxo-1-butanol as a colorless oil.

The resulting alcohol compound was dissolved in 2 ml of ethyl acetate,and 207 mg of methanesulfonyl chloride and 366 mg of triethylamine wereadded. The mixture was stirred overnight at room temperature, and thenthe precipitate was removed by filtration. The filtrate was worked up ina customary manner, and the product was purified by silica gel columnchromatography [hexane/ethyl acetate=5/1] to give 327 mg of thecaptioned compound as a pale yellow powder.

Referential Example 17 Production of(E)-3-[3-(6-chloro-1-hexenyl)phenyl]thiophene

122 mg of 5-chloro-1-pentanol was dissolved in 1 ml of methylenechloride, and under ice cooling, 322 mg of pyridinium chlorochromate wasadded. The mixture was stirred with ice cooling for 10 minutes, and thenat room temperature for 2 hours. The solution was worked up in acustomary manner to give 5-chloro-pentanal.

400 mg of 3-(3-thienyl)benzyl(triphenyl)phosphonium bromide wasdissolved in 2 ml of dimethylformamide, and under ice cooling, 37 mg of60% oily sodium hydride was added. The mixture was stirred for 15minutes, and to this solution was added an ethyl ether solution (0.6 ml)of the foregoing aldehyde compound. The mixture was stirred overnight atroom temperature, and then the solvent was evaporated. The residue wasworked up in a customary manner, and purified by silica gel columnchromatography [hexane/ethyl acetate=19/1] to give 123 mg of thecaptioned compound (a mixture of E:Z=1:1) as a pale yellow oil.

Referential Example 18 Production of(E)-3-3-(3-thienyl)phenyl]-2-propenylamine

3.8 g of (E)-3-(3-thienyl)cinnamic acid was dissolved in 50 ml ofchloroform, and 10 ml of thionyl chloride was added. The mixture wasstirred at 70 ° C. for 1 hour, and then the solvent was evaporated.Ethanol was added to the residue, and the solvent was evaporated again.The residue was purified by silica gel column chromatography [methylenechloride]to give 4.3g of ethyl (E)-3-(3-thienyl)cinnamate as pale yellowoil.

1.0 g of the resulting ester compound was reduced in a customary mannerwith lithium aluminum hydride, and then brominated by phosphorustribromide. 0.7 g of (E)-3-[3-(3-thienyl)phenyl]-2-propenyl bromideobtained thus was dissolved in 10 ml of dimethylformamide, and 0.6 g ofpotassium phthalimide was added. The mixture was stirred overnight atroom temperature, and the solution was worked up in a customary mannerto give (E)-N-[3-[3-(3-thienyl)phenyl]-2-propenyl]phthalimide. 0.7 g ofthe resulting phthalimide compound was dissolved in a mixture (3 ml) oftetrahydrofuran and ethanol (1:1), and 0.5 ml of hydrazine hydrate wasadded. The mixture was stirred at room temperature for 1 hour, and thenworked up in a customary manner to give 0.42 g of the captionedcompound.

Referential Example 19 Production of(E)-2-[3-[3-(3-thienyl)phenyl]-2-propenyloxy]ethanol

4.0 g of (E)-3-[3-(3-thienyl)phenyl]-2-propenyl bromide obtained inReference Example 18 was dissolved in 70 ml of tetrahydrofuran, and 70ml of ethylene glycol and 2.1 g of 60% oily sodium hydride were added.The mixture was heated at 100 ° C. with stirring for 1.5 hours. Thesolution was worked up in a customary manner, and then the product waspurified by silica gel column chromatography [hexane/ethyl acetate=2/1]to give 3.7 g of the captioned compound as a pale yellow oil.

When the same reaction as in Referential Example 18 is carried out using(E)-3-[4-(3-thienyl)-2-thienyl]-2-propenyl bromide instead of thestarting (E)-3-[3-(3-thienyl)phenyl]-2-propenyl bromide,(E)-2-[3-[4-(3-thienyl)-2-thienyl]-2-propenyloxy]ethanol is obtained.

Referential Example 20 Production of2-[2-3-(3-thienyl)phenoxyethoxy]ethanol

400 mg of 2-[3-(3-thienyl)phenoxy]ethanol, obtained in ReferentialExample 14, was dissolved in 5 ml of tetrahydrofuran, and under icecooling, 80 mg of 60% oily sodium hydride was added. The mixture wasstirred for 5 minutes, and then a dimethylformamide solution (2 ml) of0.22 ml of ethyl bromoacetate was added. The mixture was stirred at roomtemperature for 2 hours, and the solvent was evaporated. The residue wasworked up in a customary manner, and purified by medium-pressure liquidchromatography [silica gel column, hexane/ethyl acetate=10/1→8/1] togive 320 mg of ethyl 2-[3-(3-thienyl)phenoxy]ethoxyacetate as acolorless oil.

311 mg of the resulting ester compound was reduced by lithium aluminumhydride as the same method in Referential Example 14 to give 276 mg ofthe captioned compound as a colorless oil.

Referential Example 21 Production of5-3-(3-chloromethylbenzyloxy)-1-propenyl]-thiazole

700 mg of methyl β-(5-thiazolyl)acrylate [see Chem. Pharm. Bull., 35 823(1987)] was dissolved in 10 ml of tetrahydrofuran, and under a nitrogenatmosphere, 8.1 ml of a 1M toluene solution of diisobutylaluminumhydride was added dropwise at -70° C. The mixture was stirred at thistemperature for 50 minutes, and water and ethyl acetate were added tothe solution. The precipitate was removed by filtration, and thefiltrate was worked up in a customary manner to give 279 mg of3-(5-thiazolyl)-2-propen-1-ol as a yellow oil.

38 mg of the resulting alcohol compound and 61 mg ofα,α'-dichloro-m-xylene were dissolved in 1 ml of dimethylformamide, andunder a nitrogen atmosphere with stirring, 12 mg of 60% oily sodiumhydride was added at -42 ° C. The solution was gradually warmed to roomtemperature, and then stirred for 2 hours. The solution was worked up ina customary manner to give 37 mg of the captioned compound as acolorless oil.

Referential Example 22 Production of3-2-2-(3-bromomethylphenyl)ethoxy]ethyl]thiophene

242 mg of 2-(3-thienyl)ethanol and 167 mg of 3-bromo-2-phenethyl alcoholwere dissolved in 3 ml of benzene, and under a nitrogen atmosphere, 324mg of silver trifluoromethanesulfonate was added. The mixture wasrefluxed for 5 hours, and then ethyl ether and water were added to thesolution to extract it. The organic layer was separated, and worked upin a customary manner to give 186 mg of3-[2-[2-(3-bromophenyl)ethoxy]ethyl]thiophene as a colorless oil.

46 mg of the resulting ether compound was dissolved in 1 ml ofdimethylformamide, and 17 mg of copper cyanide was added. The mixturewas stirred s overnight at 150 ° C. To this solution was added, amixture of 39 mg of iron(II) chloride, 0.1 ml of water and 16 μl ofhydrochloric acid, and the mixture was stirred at 60 ° C. for 30minutes. The solution was extracted with ethyl ether, and the extractwas worked up in a customary manner to give 17 mg of3-[2-[2-(3cyanophenyl)ethoxy]ethyl]thiophene as a colorless oil.

17 mg of the resulting cyano compound was dissolved in 1 ml of toluene,and a 1M toluene solution (0.17 ml)of diisobutylaluminum hydride wasadded at -50° C. The mixture was stirred at this temperature for 1.5hours. Water and 0.2 ml of 1N hydrochloric acid were added to thesolution, and then the mixture was stirred at room temperature for 30minutes. The solution was extracted with ethyl ether, and the extractwas worked up in a customary manner to give 16 mg of3-[2-[2-(3-thienyl)ethoxy]ethyl]benzaldehyde as a colorless oil.

The resulting aldehyde compound was reduced with sodium borohydride inethanol, and subsequently brominated with phosphorus tribromide to givethe captioned compound as a colorless oil.

Referential Example 23 Production of3-[3-[2-(3-chloropropoxy)ethoxy]phenyl]thiophene

0.21 g of 60% oily sodium hydride was dissolved in a mixture ofdimethylsulfoxide (5 ml) and tetrahydrofuran (5 ml), and adimethylformamide solution (5 ml) of 1.08 g of trimethylsulfonium iodidewas added dropwise at 0 ° C. with stirring. To this solution, atetrahydrofuran solution(5 ml) of 1.0 g of 3-(3-thienyl)benzaldehyde wasadded at 0 ° C. with stirring. The mixture was stirred at roomtemperature for 60 hours, and then water was added to the solution. Theorganic layer was separated, and worked up in a customary manner to give0.93 g of 3-(3-thienyl)phenyloxyrane as a colorless oil.

0.93 g of the resulting epoxide compound was added to a ethyl ethersolution (30 ml) of diborane prepared from 0.33 g of aluminum chlorideand 0.1 g of sodium borohydride. The mixture was refluxed for 1 hour,and water was added to the solution. The organic layer was separated,and worked up in a customary manner, then the product was purified bysilica gel column chromatography [hexane/ethyl acetate=2/1] to give 0.26g of 2-[3-(3-thienyl)phenyl]ethanol as a white powder.

55 mg of the resulting alcohol compound was dissolved in 1 ml ofbenzene, and under a nitrogen atmosphere, 80 μl of1-bromo-3-chloropropane and 69 mg of silver trifluoromethanesulfonatewere added. The mixture was refluxed for 16 hour while interceptinglight, and then water was added to the solution. The organic layer wasseparated, and worked up in a customary manner, then the product waspurified by silica gel column chromatoraphy [hexane/ethyl acetate=5/1]to give 24 mg of the captioned compound as a colorless oil.

Referential Example 24 Production of3-3-(5-bromopentoxy)phenyl)thiophene

0.5 g of 3-(3-thienyl)phenol and 1.97 ml of 1, 5-dibromopentane weredissolved in 10 ml of dimethylformamide, and under ice cooling, 116 mgof 60% oily sodium hydride was added. The mixture was stirred at roomtemperature for 1 hour. The solvent was evaporated, and ethyl ether andwater were added to the residue to extract it. The organic layer wasworked up in a customary manner, and the product was purified by silicagel column chromatography [hexane/ethyl acetate=10/1] to give 0.83 g ofthe captioned compound as a colorless oil.

Referential Example 25 Production of5-[3-[2-(2-chloroethoxy)ethoxy]phenyl]thiazole

260 mg of 3-(5-thiazolyl)phenol, 303 mg of 2-(2-chloroethoxy)ethylmethanesulfonate [synthesized by mesylating 2-(2-chloroethoxy)ethanolwith methanesulfonyl chloride in the presence of triethylamine] and 621mg of potassium carbonate were added to 5 ml of dimethylformamide, andthe mixture was stirred at 55° C. for 5 hours. Water and ethyl acetatewere added, and the organic layer separated was worked up in a customarymanner, then the product was purified by medium-pressure liquidchromatography [silica gel column, hexane/ethyl acetate=15/2→15/7 andmethylene chloride/ethyl acetate=10/1] to give 73 mg of the captionedcompound as a colorless oil.

When the same reaction as in Referential Example 25 is carried out using3-(3-pyridyl)phenol instead of the starting 3-(5-thiazolyl)phenol,3-[3-[2-(2-chloroethoxy)ethoxy]phenyl]pyridine is obtained.

Referential Example 26 Production of1-3-2-(2-chloroethoxy)ethoxy]phenyl]imidazole

An ethyl ether solution (3 ml) of 2.35 g of 3-[2-(2-chloroethoxy)ethoxy]aniline was added to a mixture of water (23ml) and thiophosgene (0.83 ml), and the mixture was stirred at roomtemperature for 1 hour. Ethyl ether (30 ml) was added, and the organiclayer was s separated. To the ether extract, 4.0 ml of2,2-dimethoxyethylamine was added, and the mixture was stirred overnightat room temperature. The resulting solution was washed with water andthe solvent was evaporated. The residue was purified by silica gelcolumn chromatography [hexane / ethyl acetate=5/1→2/1] to give 3.41 g ofN-[3-[2-(2-chloroethoxy)ethoxy]phenyl]-N'-(2,2-dimethoxyethyl)-thioureaas a pale yellow oil.

3.3 g of the resulting thiourea compound was dissolved in a mixture ofmethanol(10 ml) and 10% hydrochloric acid (40 ml), and the mixture washeated at 100° C. with stirring for 30 minutes. The solution wasneutralized with sodium bicarbonate, and extracted with ethyl acetate.The extract was worked up in a customary manner, and the product waspurified by silica gel column chromatography [hexane / ethyl acetate=2/1→1/1] to give 0.46 g of 1-[3-[2-(2-ethoxy]phenyl]-2-mercaptoimidazole asa pale yellow oil.

0.25 g of the resulting imidazole compound was dissolved in 4 ml of 20%nitric acid, and the mixture was heated at 100° C. with stirring for 5minutes. The solution was neutralized with sodium bicarbonate, andextracted with chloroform. The extract was worked up in a customarymanner, and the product was purified by silica gel column chromatography[ethyl acetate/hexane=2/1→ethyl acetate] to give 0.16 g of the captionedcompound as a colorless oil.

Referential Example 27 Production ofN-ethyl-6,6-dimethyl-2,4-heptadiynylamine hydrochloride

A methanol solution (7.5 ml) of 0.75 ml of propargyl bromide was addeddropwise to 6 ml of a 70% aqueous solution of ethylamine with stirringand ice cooling, and the mixture was stirred for 1.5 hours. 120 mg ofcopper(I) chloride and 100 mg of hydroxylamine hydrochloride were added,and to this solution, a methanol solution(3 ml) of 5.6 mg of1-bromo-3,3-dimethyl-1-butyne [synthesized by a bromination of lithiatedtert-butylacetylene with bromine ] was added dropwise under ice cooling.The mixture was stirred at room temperature for 2 hours, and then thesolvent was evaporated. The residue was worked up in a customary manner,and the product was treated with a methanol solution of hydrogenchloride to give 0.94 g of the captioned hydrochloride as a whitecrystalline powder.

Referential Example 28 Production of(E)-5-[3-(3-thienyl)phenoxy]-2-penten-1-ol

1.3 g of 3-(3-thienyl)phenol, 1.09 ml of 3-bromopropanal dimethylacetaland 1.1 g of potassium carbonate were dissolved in 10 ml ofdimethylformamide, and the mixture was heated at 90° C. with stirringfor 6 hours. Ethyl acetate and water were added, and the organic layerseparated was worked up in a customary manner, then the product waspurified by silica gel column chromatography [hexane / ethylacetate=30/1→20/1] to give 1.0 g of 3-[3-(3-thienyl)phenoxy] propanaldimethylacetal as a colorless oil.

0.46 g of the resulting ether compound was dissolved in 5 ml oftetrahydrofuran, and 2 ml of 2N hydrochloric acid was added. The mixturewas allowed to stand at room temperature for 4 hours, and then thesolution was made basic with an aqueous solution of sodium bicarbonate.The solution was extracted with s ethyl acetate, and the extract wasworked up in a customary manner. The product was purified by silica gelcolumn chromatography [hexane / ethyl acetate =20/1→10/1] to give 0.28 gof 3-[3-(3-thienyl)phenoxy]propanal as a colorless oil.

0.28 g of the resulting aldehyde compound was dissolved in 5 ml ofbenzene, and 0.5 g of methyl (triphenylphosphoranylidene)acetate wasadded. The mixture was stirred overnight at room temperature. Thereaction solution was worked up in a customary manner, and the productwas purified by silica gel column chromatography [hexane / ethylacetate=10/1] to give 0.21 g of 5-[3-(3-thienyl)phenoxy]-2-pentenoate asa colorless oil.

143 mg of the resulting ester compound was dissolved in 3 ml oftetarahydrofuran, and under a nitrogen atmosphere, 1.02 ml of a 1Mtoluene solution of diisobutylaluminum hydride was added dropwise withstirring at -60° C. An aqueous solution of citric acid and ethyl etherwere added to the solution to extract it. The organic layer separatedwas worked up in a customary manner, and the product was purified bysilica gel column chromatography [hexane / ethyl acetate =5/1] to give90 mg of the captioned compound as a colorless oil.

Referential Example 29 Production of(E)-4-[3-(3-thienyl)benzyloxy]-2-buten-1-ol

Under a nitrogen atmosphere, 0.47 g of 60% oily sodium hydride wassuspended in 10 ml of dimethylformamide, and a dimethylformamidesolution (10 ml) of 1.0 g of 2-butyn-1,4-diol was added dropwise withstirring and ice cooling. After the mixture was stirred for 10 minutes,a dimethylformamide solution (5 ml) of 0.59 g of3-(3-bromomethylphenyl)thiophene was added. The mixture was stirred atroom temperature for 1 hour and then ethyl ether and water were added.The organic layer separated was worked up in a customary manner, and theproduct was purified by silica gel column chromatography [hexane / ethylacetate=3/1] to give 0.48 g of 4-[3-(3-thienyl)benzyloxy]-2-butyn-1-olas a colorless oil.

0.48 g of the resulting alcohol compound was dissolved in 5 ml oftetarahydrofuran, and under a nitrogen atmosphere, a tetrahydrofuransolution (5 ml) of 78 mg of lithium aluminum hydride was added. Themixture was stirred under ice cooling for 2 hours, and then at roomtemperature for 1 hour. Ethyl acetate and water were added, and theorganic layer separated was worked up in a customary manner. The productwas purified by silica gel column chromatography [hexane / ethylacetate=4/1] to give 0.28 g of the captioned compound as a colorlessoil.

Referential Example 30 Production of1-[3-(3-thienyl)phenoxy]-5-bromo-2-pentanone

0.25 g of 3-(3-thienyl)phenol was dissolved in 2.5 ml ofdimethylformamide, and 28 mg of 60% oily sodium hydride was added. Themixture was stirred at room temperature for 15 minutes, and then adimethylformamide solution (1 ml) of 0.45 g of 1,5-dibromo-2-pentanone[see J. Chem. Soc., 1948, 278] was added dropwise at -40° C. The mixturewas stirred at this temperature for 2 hours, and ethyl ether and waterwere added. The organic layer separated was worked up in a customarymanner, and the product was purified by silica gel column chromatography[hexane / ethyl acetate=30/1] to give 50 mg of the captioned compound asa colorless oil.

Referential Example 31 Production of2-(2-hydroxyethoxy)-1-3-(3-thienyl)phenoxy]propane oxy]propane

0.68 g of 1-[3-(3-thienyl)phenoxy]-2-propanol [synthesized by reducing3-(3-thienyl)phenoxyacetone, prepared by the reaction of3-(3-thienyl)phenol and monobromoacetone in the presence of potassiumcarbonate, with sodium borohydride in ethanol] was dissolved in 7 ml ofdimethylformamide, and 48 mg of 60% oily sodium hydride was added. Afterthe mixture was stirred at room temperature for 20 minutes, 0.12 ml ofethyl bromoacetate was added. The mixture was stirred at roomtemperature for 2 hours, and then ethyl ether and water were added. Theorganic layer separated was worked up in a customary manner, and theproduct was purified by silica gel column chromatography [hexane / ethylacetate=10/1] to give 0.12 g of methyl[1-methyl-2-[3-(3-thienyl)phenoxy]ethoxy]acetate as a colorless oil.

0.12 g of the resulting ester compound was dissolved in 5 ml oftetrahydrofuran, and under ice cooling, 15 mg of lithium aluminumhydride was added. The mixture was stirred at room temperature for 2hours, and ethyl acetate and water were added. The organic layerseparated was worked up in a customary manner, and the product waspurified by silica gel column chromatography [hexane / ethylacetate=3/1] to give 83 mg of the captioned compound as a colorless oil.

Referential Example 32 Production of 2-[2-[3-(3-thienyl)phenoxy]ethoxy]propanol

0.22 g of 2-[3-(3-thienyl)phenoxy]ethanol was dissolved in 7 ml oftetrahydrofuran, and 48 mg of 60% oily sodium hydride was added. Afterthe mixture was stirred at room temperature for 20 minutes, adimethylformamide solution (5 ml) of 0.14 ml of methyl α-bromopropionatewas added. The mixture was stirred at room temperature for 1.5 hours,and then ethyl ether and water were added. The organic layer separatedwas worked up in a customary manner, and the product was purified bysilica gel column chromatography [hexane / ethyl acetate=10 / 1] to give0.22 g of methyl 2-[2-[3-(3-thienyl)phenoxy] ethoxy]propionate as acolorless oil.

0.20 g of the resulting ester compound was dissolved in 5 ml oftetrahydrofuran, and reduced as in Referential Example 31 with 25 mg oflithium alminum hydride to give 0.18 g of the captioned compound as acolorless oil.

Referential Example 33 Production of(E)-N-ethyl-5-[3-(3-thienyl)-2-propenyloxymethyl]-2-furylmethylaminehydrochloride

16.8 g of 5-hydroxymethyl-2-furaldehyde was dissolved in 70 ml ofmethanol, and 14.7 ml of methyl orthoformate and 170 mg of pyridiniump-toluenesulfonate were added. After the mixture was stirred at roomtemperature for 2 hours, 350 mg of sodium bicarbonate was added . Thesolution was stirred at room temperature for 30 minutes, and then ethylether and water were added. The organic layer separated was worked up ina customary manner to give 21.6 g of 5-hydroxymethyl-2-furaldehydedimethylacetal as a pale brown oil.

Under a nitrogen atmosphere, a tetrahydrofuran solution (210 ml) of 21.3g of the resulting acetal compound was added by portion to a suspensionof 5.01 g of 60% oily sodium hydride in tetrahydrofuran (20 ml). Themixture was stirred under ice cooling for 30 minutes, and to itssolution, a tetrahydrofuran solution (150 ml) of 20.9 g of(E)-3-(3-thienyl)-2-propenyl bromide was added dropwise over 1 hour at-20° C. The solution was warmed to 0° C., and 7 ml of dimethylformamidewas added, then the mixture was stirred overnight at 5˜10° C. Water andethyl ether were added, and the organic layer separated was worked up ina customary manner to give 22.0 g of(E)-5-[3-(3-thienyl)-2-propenyloxymethyl]-2-furaldehyde dimethylacetalas a pale yellow oil.

Under a nitrogen atmosphere, 22.0 g of the resulting acetal compound wasdissolved in 650 ml of tetrahydrofuran, and 223 ml of 0.1N hydrochloricacid was added dropwise under ice cooling. The mixture was stirredovernight at 5˜10° C., and then water and ethyl ether were added. Theorganic layer separated was worked up in a customary manner, and theproduct was recrystalized from a mixture of ethyl ether and hexane togive 16.8 g of (E)-5-[3-(3-thienyl)-2-propenyloxymethyl]-2-furaldehydeas a white crystalline powder.

16.2 g of the resulting aldehyde compound was dissolved in 50 ml oftetrahydrofuran, and 90 ml of a 2.2M ethylamine - ethanol solution wasadded. The mixture was allowed to stand overnight at room temperature,and then the solvent was evaporated. An additional amount (60 ml) of a2.2M ethylamine - ethanol solution was added to the residue, and themixture was then left at room temperature for 1 hour. The solvent wasevaporated, and the residue was dissolved in 150 ml of ethanol. 2.9 g ofsodium borohydride was added, and then the mixture was stirred at roomtemperature for 1 hour. The solvent was evaporated, and methylenechloride and water were added. The organic layer separated was worked upin a customary manner, and the resulting oily free base was dissolved in300 ml of ethyl ether under ice cooling. To this solution, 150 ml of a0.5M hydrogenchloride-ethyl ether solution was added dropwise with icecooling and stirring, and the precipitate was collected by filtration togive 17.5 g of the captioned compound as a white crystalline powder.

When the same reactions as in Referantial Example 33 are carried outusing ethanol or methanol solutions of various amines instead of theethylamineethanol solution,(E)-N-methyl-5-[3-(3-thienyl)-2-propenyloxymethyl]-2-furylmethylaminehydrochloride,(E)-N-propyl-5-[3-(3-thienyl)-2-propenyloxymethyl]-2-furylmethylaminehydrochloride,(E)-N-(2-fluoroethyl)-5-[3(3-thienyl)-2-propenyloxymethyl]-2-furylmethylamineand(E)-N-cyclopropyl-5-[3-(3-thienyl)-2-propenyloxymethyl]-2-furylmethylamineare obtained.

Referential Example 34 Production ofN-cyclopropyl-2-[2-[3-(3-thienyl)phenoxy]ethoxy}ethylamine

0.36 g of 2-[3-(3-thienyl)phenoxy]ethoxyacetic acid was dissolved in 7ml of tetrahydrofuran, and under ice cooling, 110 μl of methylchloroformate and 200 μl of triethylamine were added. After the mixturewas stirred with cooling for 30 minutes, 178 μl of cyclopropylamine wasadded. The mixture was stirred at room temperature for 1 hour, and thenethyl ether and water were added. The organic layer separated was workedup in a customary manner to give 0.31 g ofN-cyclopropyl-2-[3(3-thienyl)phenoxy]ethoxyacetamide as a pale yellowoil.

0.31 g of the resulting amide compound was dissolved in 3 ml oftetrahydrofuran, and 4 ml of a 1M diborane-tetrahydrofuran solution wasadded. The mixture was refluxed for 3 hours, and water and ethyl actatewere added. The organic layer separated was worked up in a customarymanner to give 0.25 g of the captioned compound as a pale yellow oil.

When the same reactions as in Referential Example 34 are carried outusing ethylamine or 2-fluoroethylamine instead of the startingcyclopropylamine, N-ethyl-2-[2-[3-(3-thienyl)phenoxy]ethoxy]ethylamineand N-(2-fluoroethyl)-2-[2-[3-(3-thienyl)phenoxy]ethoxy]ethylamine areobtained.

Referential Example 35 Production of N-ethyl-2-[2-3-(3-thienyl)phenoxy}ethylthio]ethylamine

2-[3-(3-thienyl)phenyl]ethyl methanesulfonate, [synthesized by reacting100 mg of 2-[3-(3-thienyl)phenoxy]ethanol with 50 μl of methanesulfonylchloride and 190 μl of triethylamine in 1 ml of ethyl acetate] wasdissolved in 1.5 ml of dimethylformamide, and 68 mg of potassiumthioacetate was added. The mixture was heated at 80° C. with stirringfor 3 hours, and then water and ethyl acetate were added. The organiclayer separated was worked up in a customary manner to give 111 mg ofS-[2-[3-(3-thienyl)phenoxy]ethyl] thioacetate as a pale brown oil.

55 mg of the resulting thioester compound, 30 mg ofN-ethylchloroacetamide and 50 mg of potassium carbonate were dissolvedin 2 ml of methanol, and the mixture was stirred at room temperature for40 minutes. Water and ethyl actate were added, and the organic layerseparated was worked up in a customary manner, then the product waspurified by medium-pressure liquid chromatography [hexane / ethylacetate=2/1→1/2] to give 58 mg ofN-ethyl-2-[3-(3-thienyl)phenoxy]ethylthioaoetamide as a colorless oil.

58 mg of the resulting amide compound was dissolved in 2 ml oftetrahydrofuran, and under a nitrogen atmosphere, 1.6 ml of a 1Mdiboran-tetrahydrofuran solution was added dropwise at 0° C. The mixturewas stirred at this temperature for 30 minutes, and then IN hydrochloricacid was added to the solution to adjust its pH to 1.0. The slovent wasevaporated, and then the residue was dissolved in a mixture of water andethyl ether. After the solution was made basic with a 1N aqueoussolution of sodium hydroxide, the organic layer was separated, andworked up in a customary manner. The product was purified by silica gelcolumn chromatography [chloroform / methanol=10/1→4/1] to give 37 mg ofthe captioned compound as a colorless oil.

Referential Example 36 Production of(E,E)-3-5-(3-thienyl)-2,4-pentadienyl]benzylalcohol

46 mg of methyl (E,E)-5-(3-thienyl)-2,4-pentadienoate was dissolved in 1ml of tetrahydrofuran, and 0.59 ml of a 1M toluene solution ofdiisobutylaluminum hydride was added dropwise at -40° C. Water, 0.6 mlof 1N hydrochloric acid and ethyl acetate were added to the solution ,and the organic layer separated was worked up in a customary manner togive 40 mg of (E,E)-5-(3-thienyl)-2,4-pentadien-1-ol as a colorless oil.

20 mg of the resulting alcohol compound was dissolved in 1.5 ml of ethylacetate, and under ice cooling, an ethyl acetate solution (0.5 ml) of16.2 mg of phosphorus tribromide was added dropwise. The mixture wasstirred for 1 hour, and then the solvent was evaporated. The residue wasdissolved in 3 ml of toluene, and under a nitrogen atmosphere, 59 mg of3-(tributylstannyl)benzaldehyde and 3 mg oftetrakis(triphenylphosphine)palladium were added. After the mixture wasrefluxed for 3 hours, 1 ml of a saturated aqueous solution of potassiumfluoride was added, and the mixture was stirred at room temperature for30 minutes. Water and ethyl acetate were added, and the organic layerseparated was worked up in a customary manner. The product was purifiedby medium-pressure liquid chromatography [hexane / ethyl acetate=8/1] togive 7 mg of (E,E)-3-[5-(3-thienyl)-2,4-penta-dienyl]benzaldehyde as apale yellow oil.

6 mg of the resulting aldehyde compound was dissolved in 1 ml ofethanol, and 1 mg of sodium borohydride was added. The mixture wasstirred at room temperature for 15 minutes, and then water and ethylether were added. The organic layer separated was worked up in acustomary manner to give 6 mg of the captioned compound as a pale yellowoil.

Referential Example 37 Production of (E)-6,6-dimethyl-4-hepten-2-yn-1-ol

0.63 g of (E)-1- iodo-3,3-dimethyl-1-butene [see J. Org. Chem., 43, 4424(1978)] was dissolved in 10 ml of tetrahydrofuran, and 31 mg oftriphenylphosphine, 29 mg of copper(I) iodide, 11 mg of palladiumchloride, 1.5 ml of n-butylamine and 0.35 ml of propargyl alcohol wereadded. The mixture was stirred overnight at room temperature, and thenwater and ethyl acetate were added. The organic layer separated wasworked up in a customary manner, and the product was purified by silicagel column chromatography [hexane/ethyl acetate=2/1] to give 0.27 g ofthe captioned compound as a pale brown oil.

Referential Example 38 Production of6-methoxy-6-methyl-2,4-heptadiyn-1-ol

200 ml of a 70% aqueous solution of ethyamine, 1 g of copper(I)chloride, 5 g of hydroxylamine hydrochloride and 25 g of propargylalcohol were dissolved in 500 ml of methanol, and with ice cooling andstirring, a methanol solution (100 ml) of 74 g of1-bromo-3-methoxy-3-methyl-1-butyne was added. The mixture was stirredat room temperature for 1 hour, and then the solvent was evaporated.Water and ethyl acetate were added, and the insoluble material wasremoved by filtration. The organic layer separated was worked up in acustomary manner, and the product was purified by vacuum distillation (b.p. -97° C. / 2 mmHg ) to give 57 g of the captioned compound as acolorless oil.

Referential Example 39 Production of6-methoxy-6-methyl-4-hepten-2-yn-1-ol

1 g of 7-tert-butyldimethylsilyloxy-2-methyl-3,5-heptadiyn-2-ol[synthesized by the same reaction as Referential Example 38 usingtert-butyldimethylpropargyloxysilane and 4-bromo-2-methyl-3-butyn-2-ol]was dissolved in 10 ml of tetrahydrofuran, and under ice cooling, 190 mgof lithium alminum hydride was added. The mixture was stirred at thistemperature for 1 hour, and then was poured into ice-cold water. Theresulting solution was extracted with ethyl ether, and the extract wasworked up in a customary manner, then purified by silica gel columnchromatography [hexane / ethyl acetate =15/1] to give 0.80 g of7-tert-butyldimethylsilyloxy-2-methyl-3-hexen-5-yn-2-ol.

The resulting en-yne compound (800 mg) was dissolved in 10 ml ofdimethylformamide, and under a nitrogen atmosphere and ice cooling, 150mg of 60% oily sodium hydride was added. The mixture was stirred underice cooling for 10 minutes, and 0.34 ml of dimethylsulfate was added.The reaction solution was stirred at this temperature for 1 hour and atroom temperature for 1 hour, then poured into ice-cold water. Theresulting solution was extracted with ethyl ether, and the extract wasworked up in a customary manner.

The resulting methoxy compound was dissolved in 10 ml oftetrahydrofuran, and under ice cooling, 4 ml of a 1M tetrabutylammoniumfluoride-tetrahydrofuran solution was added. The mixture was stirred atthis temperature for 1 hour, and then poured into ice water. Theresulting solution was extracted with ethyl ether, and the extract wasworked up in a customary manner, then purified by silica gel columnchromatography [hexane / ethyl acetate=4/1] to give 280 mg of thecaptioned compound as a colorless oil.

Referential Example 40 Production of 6,6-dimethyl-4-heptynylmethanesulfonate

0.81 g of tert-butylacetylene was dissolved in 19 ml of tetrahydrofuran,and 6.1 ml of a 0.55M n-butyllithium-hexane solution was added dropwisewith stirring at -78° C. After the mixture was stirred at thistemperature for 1 hour, 2.2 g of3-bromo-1-(2-tetrahydropyranyloxy)propane was added. The solution waswarmed to the room temperature, and then heated at 80° C. with stirringfor 8 hours. The reaction mixture was poured into the ice water, andethyl ether was added. The organic layer separated was worked up in acustomary manner, and the product was purified by silica gel columnchromatography [hexane / ethyl acetate=20 /1] to give 0.90 g of6,6-dimethyl-1-(2-tetrahydropyranyloxy)-4-heptyne.

0.90 g of the resulting heptyne compound was dissolved in 18 ml ofmethanol, and 6 ml of 1N hydrochloric acid was added. The mixture wasstirred at s room temperature for 2 hour, and then the solvent wasevaporated. Ethyl ether and a saturated aqueuos solution of sodiumbicarbonate was added , and the organic layer separated was worked up ina customary manner. The product was purified by silica gel columnchromatography [hexane / ethyl acetate=20/1] to give 0.26 g of6,6-dimethyl-4-heptyn-1-ol.

100 mg of the resulting alcohol compound was dissolved in 1 ml of ethylacetate, and 60 μl of methanesulfonyl chloride and 200 μl oftriethylamine were added. The mixture was stirred at room temperaturefor 1 hour, and then the precipitate of triethylamine hydrochloride wasremoved by filtration. The filtrate was diluted with ethyl acetate, andwashed succesively with a saturated aqueous solution of sodiumbicarbonate, 1N hydrochloric acid and a saturated aqueous slution ofsodium chloride, then worked up in a customary manner to give 150 mg ofthe captioned compound as a colorless oil.

Referential Example 41 Production of 5-[3-(3-thienyl)phenoxy]pentylamine

0.65 g of 3-[3-(5-bromopentyloxy)phenyl]thiophene, 0.37 g of potassiumphthalimide and 0.14 g of potassium carbonate were dissolved in 5 ml ofdimethylformamide, and the mixture was heated at 50° C. with stirringfor 5 hours. Ethyl acetate and water were added, and the organic layerseparated was worked up in a customary manner. The product was purifiedby silica gel column chromatography [hexane / ethyl acetate=7/1 →5/1] togive 0.36 g of N-[5-[3-(3-thienyl)phenoxy]pentyl] phthalimide as acolorless oil.

0.36 g of the resulting phthalimide compound was dissolved in a mixtureof ethanol (10 ml) and tetrahydrofuran (3 ml), and 1 ml of hydrazinehydrate was added. The mixture was stirred at room temperature for 2hours, and then chloroform and water were added. The organic layerseparated was worked up in a customary manner, and the product waspurified by silica gel column chromatography [chloroform / methanol 3/1→1/1] to give 0.17 g of the captioned compound as a pale yellow oil.

When the same reaction as in Referential Example 39 is carried out using3-[3-[2-(2-chloroethoxy)ethoxy]phenyl]thiophene instead of using thestarting 3-[3-(5-bromopentyloxy)phenyl] thiophene,2-[2-[3-(3-thienyl)phenoxy]ethoxy ]ethylamine is obtained.

Referential Example 42 Production of(E)-N-ethyl-N-(7,7,7-trifluoro-6-trifluoromethyl-6-hydroxy-2-hepten-4-ynyl)-2-2-[3-(3-thienyl)phenoxy]ethoxy]ethylamine

1.9 g of N-ethyl-2-[2-[3-(3-thienyl)phenoxy]ethoxy]ethylamine and 2.7 gof potassium carbonate were dissolved in 15 ml of dimethylformamide, anda dimethylformamide solution (5 ml) of 1.43 g of(E)-5-bromo-3-penten-1-ynyl(trimethyl)silane [synthesized by mesylating3-hydroxy-4-penten-1-ynyl(trimethyl)silane, prepared fromtrimethylsilylacetylene and acrolein, with methanesulfonyl chloride andtriethylamine, and subsequently treating the mesylated product withtrimethylammonium bromide] was added dropwise. The mixture was stirredat room temperature for 30 minutes, and then ethyl acetate and waterwere added. The organic layer separated was worked up in a customarymanner, and the product was purified by silica gel column chromatography[methylene chloride / methanol=20/1] to give 2.3 g of(E)-N-ethyl-N-(5-trimethylsilyl-2-penten-4-ynyl)-2-[2-[3-(3-thienyl)phenoxy]ethoxy]ethylamine as a colorless oil.

2.0 g of the resulting allylamine compound was dissolved in a mixture ofmethanol (5 ml) and tetrahydrofuran (5 ml), and 10 ml of a saturatedaqueous solution of potassium fluoride was added. The mixture wasstirred overnight at room temperature, and then ethyl acetate and waterwere added. The organic layer s separated was worked up in a customarymanner, and the product was purified by silica gel column chromatography[methylene chloride / methanol=100/1] to give 1.3 g of(E)-N-ethyl-N-(2-penten-4-ynyl)-2-[2-[3-(3-thienyl)phenoxy)ethoxy]ethylamine as a colorless oil.

240 mg of the above-obtained compound was dissolved in 6 ml oftetrahydrofuran, and under a nitrogen atmosphere, 0.48 ml of a 1.6Mn-butyllithiumhexane solution was added at -78° C. After the mixture wasstirred at this temperature for 40 minute, 0.5 ml of hexafluoroacetonewas added. The mixture was stirred at -78° C. for 1 hour, and then ethylacetate and water were added. The organic layer separated was worked upin a customary manner, and the product was purified by silica gel columnchromatography [methylene chloride / methanol =50/1] to give 185 mg ofthe captioned compound as a colorless oil.

Referential Example 43 Production of 3-(3-thienyloxy)propanol

68 mg of sodium was added to 10 ml of 1,3-propandiol, and the mixturewas stirred at room temperature for 1 hour. The reaction solution waswarmed to 70° C., and to this solution were added, 126 μl of3-bromothiophene, 13 mg of copper(I) iodide and 16 mg of copper(II)oxide. The mixture was heated at 150° C. with stirring for 20 hours, andthen poured into the ice-cold water. The resulting solution wasneutralized with diluted hydrochloric acid, and extracted with ethylether. The extract was worked up in a customary manner, and the productwas purified by medium-pressure liquid chromatography [silica gelcolumn, hexane ethyl acetate=20/1→5/1] to give 49 mg of the captionedcompound as a white crystal.

Referential Example 44 Production of(E)-N-ethyl-N-(4-oxopentyl)-6,6-dimethyl-2-hepten-4-ynylamine

0.33 g of 2-(3-chloropropyl)-2-methyl-1,3-dioxorane, 0.33 g of potassiumiodide, 0.69 g of potassium carbonate and 0.61 g of(E)-N-ethyl-6,6-dimethyl-2-hepten-4-ynylamine hydrochloride weredissolved in 5 ml of dimethylformamide, and the mixture was stirred at100° C. for 14 hours. Water and ethyl acetate were added, and then theorganic layer separated was worked up in a customary manner. The productwas purified by silica gel column chromatography [hexane / ethylacetate=1/1] to give 0.51 g of ethylene acetal of the captioned ketone.

The resulting ethylene acetal compound (0.51 g) was dissolved in 5 ml oftetrahydrofuran, and 5 ml of 1N hydrochloric acid was added. The mixturewas stirred at room temperature for 2 hours, and then a saturatedaqueous solution of sodium bicarbonate was added to the mixture to makeit basic. Ethyl acetate and water were added, and the organic layerseparated was worked up in a customary manner to give 0.43 g of thecaptioned compound as a colorless oil.

Referential Example 45 Production of 3-thienylmethoxyacetic acid

1.0 g of 3-thiophenemethanol was dissolved in 6 ml of dimethylformamide,and under ice cooling, 0.36 g of 60% oily sodium hydride and 1 ml ofethyl bromoacetate were added. The mixture was stirred at roomtemperature for 15 hours, and then worked up in a customary manner. Theproduct was purified by silica gel column chromatography [hexane / ethylacetate=6/1] to give 0.9 g of ethyl 3-thienylmethoxyacetate as acolorless oil.

0.9 g of the resulting ether compound was dissolved in 10 ml of ethanol,and an aqueous solution(10 ml) of 1.44 g of sodium hydroxide was added.The mixture was refluxed for 4 hours, and then acetic acid was added tothe solution to acidify it. The solvent was evaporated, and ethylacetate and water were added. The organic layer separated was worked upin a customary manner to give 0.75 g of the captioned compound as acolorless oil.

Referential Example 46 Production of(E)-3-(N-ethyl-6,6-dimethyl-2-hepten-4-ynylaminomethyl)phenylacetic acid

240 mg of(E)-N-ethyl-N-(6,6-dimethyl-2-hepten-4-ynyl)-3-bromomethylbenzylaminewas dissolved in 4 ml of dimethylformamide, and 61 mg of sodium cyanidewas added. The mixture was stirred overnight at room temperature, andthen ethyl ether and water were added. The organic layer separated wasworked up in a customary manner to give 195 mg of(E)-3-(N-ethyl-6,6-dimethyl-2-hepten-4-ynylaminomethyl)phenylacetonitrileas a colorless oil.

195 mg of the resulting nitrile compound was dissolved in 6 ml ofethanol, and a 3N aqueous solution (2ml) of sodium hydroxide was added.The mixture was refluxed for 3 hours, and then acidified with 1Nhydrochloric acid. Ethyl acetate and water were added, and the organiclayer separated was worked up in a customary manner. The product waspurified by silica gel column chromatography [ethyl acetate /methanol=20/1] to give 176 mg of the captioned compound as a colorlessoil.

Referential Example 47 Production of(E)-N-ethyl-N-(6,6-dimethyl-2-hepten-4-ynyl)-3-aminomethylbenzylamine

0.57 g of potassium phthlimide was suspended in 20 ml ofdimethylformamide, and 2.42 g of α,α-dibromo-m-xylene was added. Themixture was stirred overnight at room temperature, and then ethyl etherand water were added. The organic layer separated was worked up in acustomary manner, and the product was purified by silica gel columnchromatography [hexane / ethyl acetate=10/1] to give 0.52 g ofN-(3-bromomethylbenzyl)phthalimide as a white crystalline powder.

0.50 g of the resulting bromo compound was dissolved in 20 ml ofdimethylformamide, and 0.42 g of potassium carbonate, 0.21 g ofpotassium iodide and 0.37 g of(E)-N-ethyl-6,6-dimethyl-2-hepten-4-ynylamine hydrochloride were added.The mixture was stirred overnight at room temperature. Ethyl ether andwater were added, and the organic layer separated was worked up in acustomary manner. The resulting phthalimide compound was dissolved in 10ml of tetrahydrofuran, and 0.22 ml of hydrazine hydrate was added. Themixture was stirred overnight at room temperature, and then theprecipitate was removed by filtration. The filtrate was worked up in acustomary manner, and the product was purified by silica gel columnchromatography [ethyl acetate] to give 0.30 g of the captioned compoundas a pale yellow oil.

Referential Example 48 Production of(E,E)-N-ethyl-N-(6-methoxy-6-methyl-2-hepten-4-ynyl)-5-(3-hydroxy-1-propenyl)-2-furylmethylamine

0.36 g of 5-hydroxymethyl-2-furaldehyde was dissolved in 10 ml of ethylether, and under a nitrogen atmosphere, a ethyl ether solution (2 ml) of0.25 g of phosphorus tribromide was added dropwise at 0° C. After themixture was stirred at room temperature for 30 minutes, 0.70 g ofpotassium carbonate and a dimethylformamide solution (15 ml) of 0.62 gof (E)-N-ethyl-6-methoxy-6-methyl-2-hepten-4-ynylamine hydrochloridewere added. The mixture was stirred overnight at room temperature, andthen worked up in a customary manner. The product was purified by silicagel column chromatography [hexane/ethyl acetate=2/1] to give 0.62 g of(E)-N-ethyl-N-(6-methoxy-6-methyl-2-hepten-4-ynyl)-5-formyl-2-furylmethylamineas a pale yellow oil.

A dimethoxyethane solution (2 ml) of 200 mg of the resulting formylcompound was added to a mixture of 60% oily sodium hydride(28 mg), ethyldiethylphosphonoacetate (55 mg) and dimethoxyethane (1 ml). The mixturewas stirred at room temperature for 30 minutes, and then ethyl acetateand water were added. The organic layer separated was worked up in acustomary manner to give 246 mg of ethyl(E,E)-β-[5-(N-ethyl-6-methoxy-6-methyl-2-hepten-4-ynylaminomethyl)-2-furyl]acrylate.

232 mg of the resulting ester compound was dissolved in 10 ml oftetrahydrofuran, and 1.61 ml of a 1M diisobutylaluminum hydride-toluenesolution was added dropwide with stirring at -40° C. After 5 ml of waterand 1.6 ml of 1N hydrochloric acid were added, the mixture was stirredat room temperature for 30 minutes, and then 20 ml of a saturatedaqueous solution of sodium bicarbonate was added. The mixture wasstirred at room temperature for 2 hours, and ethyl ether and water wereadded. The organic layer separated was worked up in a customary manner,and the product was purified by silica gel column chromatography [ethylacetate=1/1] to give 175 mg of the captioned compound as a pale yellowoil.

When ethyl(E)-3-(N-ethyl-6,6-dimethyl-2-hepten-4-ynylaminomethyl)cinnamate,prepared by using 3-hydroxymethylbenzaldehyde and(E)-N-ethyl-6,6-dimethyl-2-hepten-4-ynylamine hydrochloride instead ofthe starting 5-hydroxymethyl-2-furaldehyde and(E)-N-ethyl-6-methoxy-6-methyl-2-hepten-4-ynylamine hydrochloride as inReferential Example 46, is hydrolyzed with potassium hydroxide,(E)-3-(N-ethyl-6,6-dimethyl-2-hepten-4-ynylaminomethyl) cinnamic acid isobtained.

Referential Example 49 Production of(E)-N-ethyl-N-(6-methoxy-6-methyl-2-hepten-4-ynvl)-5-hydroxymethyl-2-oxazolylmethylamine

111 mg of ethyl 2-methyloxazol-5-carboxylate [see J. Heterocyclic Chem.,17, 721 (1980)] was dissolved in 5 ml of carbon tetrachloride, 133 mg ofN-bromosuccinimide and 5 mg of dibenzoyl peroxide was added. The mixturewas refluxed for 3 hours under the irradiation of the artificial sunlight, and then the solvent was evaporated. The residue was purified bysilica gel column chromatography [hexane/ethyl acetate=3/1] to give 110mg of ethyl 2-bromomethyloxazole-5-carboxylate as a pale yellow oil.

25 mg of the resulting brominated compound was dissolved in 1 ml ofdimethylformamide, and 26 mg of(E)-N-ethyl-6-methoxy-6-methyl-2-hepten-4-ynylamine hydrochloride and 22mg of potassium carbonate were added. The mixture was stirred overnightat room temperature and then ethyl ether and water were added. Theorganic layer separated was worked up in a customary manner, and theproduct was purified by silica gel column chromato-graphy [ethylacetate=3/1] to give 19 mg of ethyl(E)-2-(N-ethyl-6-methoxy-6-methyl-2-hepten-4-ynylaminomethyl)oxazole-5-carboxylateas a colorless oil.

19 mg of the resulting amino compound was dissolved in 3 ml of ethanol,and 3.2 mg of sodium borohydride and 11 mg of calucium chloride wasadded. The mixture was stirred at room temperature for 3 hours, and thenethyl acetate and water were added. The organic layer separated wasworked up in a customary manner, and the product was purified by silicagel column chromatography [ethyl acetate / hexane=3/1] to give 10 mg ofthe captioned compound as a colorless oil.

When the same reactions as in Referential Example 49 are carried outusing ethyl 4-bromomethylthiazol-2-carboxylate [see Ann., 1981, 623] orethyl 5-bromoethylisoxazol-3-carboxylate [synthesized by brominatingethyl 5-methylisoxazole-5-carboxylate [see J. Heterocyclic Chem., 19,557(1982)] with N-bromosuccimide in carbon tetrachloride] insted of thestarting ethyl 4-bromomethyloxazol-2-carboxylate,(E)-N-ethyl-N-(6-methoxy-6-methyl-2-hepten-4-ynyl)-2-hydroxymethyl-4-thiazolylmethylamine and(E)-N-ethyl-N-(6-methoxy-6-methyl-2-hepten-4-ynyl)-3-hydroxymethyl-5-isoxazolylmethylamineare obtained.

Referential Example 50 Production of(E)-N-ethyl-N-(6,6-dimethyl-2-hepten-4-ynyl)-3-[2-hydroxy-3-(3-thienylmethoxy)propyl]benzylamine

62 mg of 3(3-chlromethylphenyl)-1-(3-thienylmethoxy)-2-propanol[synthesized by the epoxidation reaction of(E)-3-[3-(3-chloromethylphenyl)-2-propenyloxymethyl]thiophene withm-chloroperbenzoic acid in benzene, followed by the reduction withlithium aluminun hydride in ethyl ether] was dissolved in 1 ml ofdimethylformamide, and 47 mg of(E)-N-ethyl-6,6-dimethyl-2-hepten-4-ynylamine hydrochloride, 49 mg ofpotassium carbonate and 3 mg of potassium iodide were added. The mixturewas stirred overnight at room temperature, and then ethyl ether andwater were added. The organic layer separated was worked up in acustomary manner, and the product was purified by medium-pressure liquidchromatography [silica gel column, hexane/ ethyl acetate=5/1→4/1] togive 61 mg of the captioned compound as a colorless oil.

Referential Example 51 Production of(E)-N-ethyl-N-(6,6-dimethyl-2-hepten-4-ynyl)-2-hydroxy-5-[3-(3-thienyl)phenoxy]pentylamine

0.22 g of 1,2-epoxy-5-[3-(3-thienyl)phenoxy]pentane [synthesized by theepoxidation reaction of 3-[3-(4-pentenyloxy)phenyl]thiophene, preparedfrom 3-(3-thienyl)phenol and 5-bromo-1-pentene, with m-chloroperbenzoicacid in benzene] was dissolved in 4 ml of ethanol, and 0.22 g of(E)-N-ethyl-6,6-dimethyl-2-hepten-4-ynylamine hydrochloride, 0.34 ml oftriethylamine were added. The mixture was refluxed for 5 hours, and thenthe solvent was evaporated. The residue was purified by silica gelcolumn chromatography [chloroform / ethyl acetate=20/1] to give 0.23 gof the captioned compound as a pale yellow oil.

Effect of the Invention

Compound of the invention inhibit biosynthesis of cholesterol in mammalsby inhibiting their squalene epoxidase, and thereby lower their bloodcholesterol values. Thus, it can be expected that these compounds areeffective as an agent for the treatment and prophylaxis of diseasescaused by excess of cholesterol, for example, obesity, hyperlipemia andarteriosclerosis and heart and encephalic diseases accompanying them.

What we claim is:
 1. Substituted amine derivatives represented by thefollowing formula (I) and their nontoxic salts: ##STR22## wherein R is athienyl group; andQ denotes (a) a group represented by the formula##STR23## wherein C, D, E, F and G are the same or different and eachdenotes an oxygen atom, sulfur atom, carbonyl group, group representedby the formula --CHR⁶ --, group represented by the formula --CR^(c) ═ orgroup represented by the formula --NR⁴ --, wherein R^(b), R^(c) andR^(d) are the same or different and each denotes a hydrogen atom orlower alkyl group; R^(a) denotes a hydrogen atom, halogen atom, hydroxylgroup, cyano group, lower alkyl group or lower alkoxy group, providedthat except that each pair of C and F, C and G, or D and G are the sameor different and can denote oxygen atom(s), sulfur atom(s) or group(s)represented by the formula --NR^(d) --, it is impossible that at leasttwo of C, D, E, F and G are simultaneously oxygen atom(s), sulfuratom(s) or group(s) represented by the formula --NR^(d) --, and it isimpossible that at least two of C, D, E, F and G simultaneously denotecarbonyl groups, and further when double bond(s) and oxygen atom(s),sulfur atom(s) or group(s) represented by the formula --NR^(d) --coexist in the chain formed by C, D, E, F and G, they do not adjoin oneanother, or (b) a group represented by the formula: ##STR24## wherein H,I, J, and K are the same or different and each denotes an oxygen atom,sulfur atom, carbonyl group, group represented by the formula --CHR^(f)--, group represented by the formula --CR^(g) --═ or group representedby the formula --NR^(b) --, wherein R^(f), R^(g) and R^(h) are the sameor different and each denotes a hydrogen atom or lower alkyl group; Ldenotes a carbonyl group, group represented by the formula --CHR^(i) --or group represented by the formula --CR^(j) --═, wherein R^(i) andR^(j) are the same or different and each denotes a hydrogen atom orlower alkyl group; and R^(e) denotes a hydrogen atom, halogen atom,hydroxyl group, cyano group, lower alkyl group or lower alkoxy group,provided that except that H and K are the same or different and each candenote an oxygen atom, sulfur atom or group represented by the formula--NR^(h) --, it is impossible that at least two of H , I, J, and Ksimultaneously denote oxygen atom(s), sulfur atom(s) or group(s)represented by the formula --NR^(h) --, and it is impossible that atleast two of H, I, J, and K simultaneously denote carbonyl groups, andfurther when double bond(s) and oxygen atom(s), sulfur atom(s) orgroup(s) represented by the formula --NR^(h) -- coexist in the chainformed by H, I, J, K and L, they do not adjoin one another; R¹ denotes ahydrogen atom, lower alkyl group, lower haloalkyl group, lower alkenylgroup, lower alkynyl group or cycloalkyl group; R², R³, R⁴ and R⁵ arethe same or different and each denotes a hydrogen atom, halogen atom orlower alkyl group, or R² and R⁴ and/or R³ and R⁵ combine to denote asingle bond; R⁶ and R⁷ are the same or different and each denotes ahydrogen atom, halogen atom or lower alkyl group, or R⁶ and R⁷ combineto denote a single bond; R⁸ and R⁹ are the same or different and eachdenotes a fluorine atom, trifluoromethyl group or lower alkyl group, orR⁸ and R⁹ combine to form a cycloalkane together with the adjacentcarbon atom; and R¹⁰ denotes a hydrogen atom, fluorine atom,trifluoromethyl group, acetoxy group, lower alkyl group or lower alkoxygroup. 2.(E,E)-N-ethyl-N-(6-methoxy-6-methyl-2-hepten-4-ynyl)-3-[3-(3-thienyl)-2-propenyloxymethyl] benzylamine or pharmaceutically acceptable saltthereof.
 3. A pharmaceutical composition for treatinghypercholesterolemia, hyperlipemia or arteriosclerosis, comprising apharmaceutically effective amount of a compound of formula (I) as setforth in claim 1, or a pharmaceutically acceptable salt thereof and apharmaceutically acceptable carrier or diluent.
 4. The substituted aminederivatives and their non-toxic salts of claim 1 wherein Q denotes agroup represented by one of the following formula: ##STR25## wherein Xdenotes an oxygen atom, sulfur atom or a group represented by theformula --NR^(d) --, wherein R^(d) and R^(a) are as defined above. 5.The substituted amine derivatives and their non-toxic salts of claim 1wherein Q denotes a group represented by one of the following formula:##STR26## wherein Y and Y' are the same or different and each denotes anoxygen atom, sulfur atom or a group represented by the formula --NR^(d)--, wherein R^(d) and R^(c) are as defined above.
 6. The substitutedamine derivatives and their non-toxic salts of claim 1 wherein R¹ is amethyl, ethyl, propyl, allyl, propargyl, cyclopropyl or 2-fluoroethylgroup;R², R³, R⁴ and R⁵ are simultaneously hydrogen atoms, or R² and R⁴and/or R³ and R⁵ combine to form a single bond and the remainder of R²,R³, R⁴ and R⁵ are the same or different and each represents a hydrogenatom or fluorine atom; R⁶ and R⁷ are hydrogen atoms or R⁶ and R⁷ combineto form a single bond; R⁸ and R⁹ are the same or different and eachrepresents a fluorine atom, methyl group, ethyl group, propyl group ortrifluoromethyl group, or R⁸ and R⁹ combine together with the adjacentcarbon to form a cyclopropane ring; and R¹⁰ is a hydrogen atom, fluorineatom, methyl group, ethyl group, propyl group, trifluoromethyl group,methoxy group, ethoxy group, propoxy group or acetoxy group.
 7. Thesubstituted amine derivatives and their nontoxic salts of claim 1wherein R¹ is a methyl, ethyl, propyl, allyl, propargyl, cyclopropyl or2-fluoroethyl group.
 8. The substituted amine derivatives and theirnontoxic salts of claim 1 wherein R², R³, R⁴ and R⁵ are simultaneouslyhydrogen atoms, or R² and R⁴ and/or R³ and R⁵ combine to form a singlebond and the remainder of R², R³, R⁴ and R⁵ are the same or differentand hydrogen atom(s) or fluorine atom(s).
 9. The substituted aminederivatives and their nontoxic salts of claim 1 wherein R⁶ and R⁷ arehydrogen atoms or R⁶ and R⁷ combine to form a single bond.
 10. Thesubstituted amine derivatives and their nontoxic salts of claim 1wherein R⁸ and R⁹ are the same or different and each denotes a fluorineatom, methyl group, ethyl group, propyl group or trifluoromethyl group,or R⁸ and R⁹ combine togehter with the adjacent carbon to form acyclopropane ring.
 11. The substituted amine derivatives and theirnontoxic salts of claim 1 wherein R¹⁰ is a hydrogen atom, fluorine atom,methyl group, ethyl group, propyl group, trifluoromethyl group, methoxygroup, ethoxy group, propoxy group or acetoxy group.
 12. A method oftreating or preventing hypercholesterolemia, hyperlipemia orarteriosclerosis in an individual in need of such treatment whichcomprises administering to said individual a therapeutically effectiveamount of a compound of formula (I) as set forth in claim 1 or apharmaceutically acceptable salt thereof.
 13. A squalene oxidaseinhibitor comprising a compound of general formula of claim 1 or apharmaceutically acceptable salt thereof.